List of phenyltropanes: Difference between revisions
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|''para''-isopropylphenyltropane<br>''11s''||CH(CH<sub>3</sub>)<sub>2</sub>||597 ± 52||191 ± 9.5||75000 ± 5820||0.3||126 |
|''para''-isopropylphenyltropane<br>''11s''||CH(CH<sub>3</sub>)<sub>2</sub>||597 ± 52||191 ± 9.5||75000 ± 5820||0.3||126 |
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|''para''-vinylphenyltropane |
|''para''-vinylphenyltropane<br>''11t''||CH-CH<sub>2</sub>||1.24 ± 0.2||9.5 ± 0.8||78 ± 4.1||7.7||62.9 |
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|''11u''||C(=CH<sub>2</sub>)CH<sub>3</sub>||14.4 ± 0.3||3.13 ± 0.16||1330 ± 333||0.2||92.4 |
|''11u''||C(=CH<sub>2</sub>)CH<sub>3</sub>||14.4 ± 0.3||3.13 ± 0.16||1330 ± 333||0.2||92.4 |
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| ''trans''-3''β''-(4′-propenyl)phenyltropane<br>''11v''||''trans''-CH=CHCH<sub>3</sub>||5.29 ± 0.53||11.4 ± 0.28||1590 ± 93||2.1||300 |
| ''trans''-3''β''-(4′-propenyl)phenyltropane<br>''11v''||''trans''-CH=CHCH<sub>3</sub>||5.29 ± 0.53||11.4 ± 0.28||1590 ± 93||2.1||300 |
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|''para''-allylphenyltropane |
|''para''-allylphenyltropane<br>''11x''||CH<sub>2</sub>CH=CH<sub>2</sub>||32.8 ± 3.1||28.4 ± 2.4||2480 ± 229||0.9||75.6 |
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|''para''-alkynylphenyltropane{{verification needed|date=February 2016}}<br>''11y''||C≡CH||1.2 ± 0.1||4.4 ± 0.4||83.2 ± 2.8||3.7||69.3 |
|''para''-alkynylphenyltropane{{verification needed|date=February 2016}}<br>''11y''||C≡CH||1.2 ± 0.1||4.4 ± 0.4||83.2 ± 2.8||3.7||69.3 |
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|''para''-propynylphenyltropane |
|''para''-propynylphenyltropane<br>''11z''||C≡CCH<sub>3</sub>||2.37 ± 0.2||15.7 ± 1.5||820 ± 46||6.6||346 |
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|''para''-phenylphenyltropane<br>''11aa''||Ph||10.3 ± 2.6<sup>'''f'''</sup><br>29.4 ± 3.8<sup>'''ɑ'''</sup>||—||—||—||— |
|''para''-phenylphenyltropane<br>''11aa''||Ph||10.3 ± 2.6<sup>'''f'''</sup><br>29.4 ± 3.8<sup>'''ɑ'''</sup>||—||—||—||— |
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Revision as of 22:48, 13 February 2016
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Phenyltropanes are a family of chemical compounds originally derived from structural modification of cocaine. These compounds present many different avenues of research into therapeutic applications, particularly in addiction treatment. Uses vary depending on their construction and structure-activity relationship ranging from the treating of cocaine dependency to understanding the dopamine reward system in the human brain to treating Alzheimer's & Parkinson's diseases. (Since 2008 there have been continual additions to the list and enumerations of the plethora of types of chemicals that fall into the category of this substance profile.) Certain phenyltropanes can even be used as a smoking cessation aid (c.f. RTI-29). Many of the compounds were first elucidated in published material by the Research Triangle Institute and are thus named with "RTI" serial-numbers. Similarly, a number of others are named for Sterling-Winthrop pharmaceuticals ("WIN" serial-numbers) and Wake Forest University ("WF" serial-numbers).
2-Carboxymethyl esters (phenyl-methylecgonines)
Like cocaine, phenyltropanes are considered a 'typical' or 'classical' (i.e. "cocaine-like") DAT re-uptake pump ligands in that they stabilize an "open-to-out" conformation on the dopamine transporter; despite the extreme similarity to phenyltropanes, benztropine and others are in suchwise not considered "cocaine-like" and are instead considered atypical inhibitors insofar as they stabilize what is considered a more inward-facing (closed-to-out) conformational state.[2]
Considering the differences between PTs and cocaine: the difference in the length of the benzoyloxy and the phenyl linkage contrasted between cocaine and phenyltropanes makes for a shorter distance between the centroid of the aromatic benzene and the bridge nitrogen of the tropane in the latter PTs. This distance being on a scale of 5.6 Å for phenyltropanes and 7.7 Å for cocaine or analogs with the benzoyloxy intact.[a] The manner in which this sets phenyltropanes into the binding pocket at MAT is postulated as one possible explanation to account for PTs increased behavioral stimulation profile over cocaine.[b]
Blank spacings within tables for omitted data use "no data", "?", "-" or "—" interchangeably.
| Short Name (Singh's #) |
X (para-substitution) | DA [3H]WIN 35428 |
5HT [3H]paroxetine |
NE [3H]nisoxetine |
selectivity 5-HTT/DAT |
selectivity NET/DAT |
|---|---|---|---|---|---|---|
| cocaine | H | 102 ± 12 241 ± 18ɑ |
1045 ± 89 112 ± 2b |
3298 ± 293 160 ± 15c |
10.2 0.5d |
32.3 0.7e |
| Troparil WIN 35,065-2 (β-CPT) 11a |
H | 23 ± 5.0 49.8 ± 2.2ɑ |
1962 ± 61 173 ± 13b |
920 ± 73 37.2 ± 5.2c |
85.3 3.5d |
40.0 0.7e |
| para-fluorophenyltropane WIN 35,428 (β-CFT) 11b |
F | 14 (15.7 ± 1.4) 22.9 ± 0.4ɑ |
156 (810 ± 59) 100 ± 13b |
85 (835 ± 45) 38.6 ± 9.9c |
51.6 4.4d |
53.2 1.7e |
| para-nitrophenyltropane 11k |
NO2 | 10.1 ± 0.10 | ? | ? | ? | ? |
| para-aminophenyltropane RTI-29[4] 11j |
NH2 | 9.8 24.8 ± 1.3g |
5110 | 151 | — | — |
| para-chlorophenyltropane RTI-31 11c |
Cl | 1.12 ± 0.06 3.68 ± 0.09ɑ |
44.5 ± 1.3 5.00 ± 0.05b |
37 ± 2.1 5.86 ± 0.67c |
39.7 1.3d |
33.0 1.7e |
| para-methylphenyltropane RTI-32 11f |
Me | 1.71 ± 0.30 7.02 ± 0.30ɑ |
240 ± 27 19.38 ± 0.65b |
60 ± 0.53e 8.42 ± 1.53c |
140 2.8d |
35.1 1.2e |
| para-bromophenyltropane RTI-51 11d |
Br | 1.81 (1.69) ± 0.30 | 10.6 ± 0.24 | 37.4 ± 5.2 | 5.8 | 20.7 |
| para-iodophenyltropane Iometopane (β-CIT, RTI-55) 11e |
I | 1.26 ± 0.04 1.96 ± 0.09ɑ |
4.21 ± 0.3 1.74 ± 0.23b |
36 ± 2.7 7.51 ± 0.82c |
3.3 0.9d |
28.6 3.8e |
| para-ethylphenyltropane RTI-83 11g |
Et | 55 ± 2.1 | 28.4 ± 3.8 | 4030 ± 381 | 0.5 | 73.3 |
| cis-3β-(4′-propenyl)phenyltropane RTI-11w 11w |
cis-CH=CHCH3 | 15 ± 1.2 | 7.1 ± 0.71 | 28,000 ± 300 | 0.5 | 1867 |
| RTI-298[5] | –≡–Ph | 3.7 | 46.8 | 347 | — | — |
| RTI-436 | –CH=CHPh | 3.09 | 335 (31) | 1960 (1181) | — | — |
| RTI-430 | –C≡C(CH2)2Ph | 6.28 | 2128 (198) | 1470 (886) | — | — |
| Tamagnan[1] | p-thiophene | 12 | 0.017 | 189 | — | — |
| para-hydroxyphenyltropane 11h |
OH | 12.1 ± 0.86 | — | — | — | — |
| para-methoxyphenyltropane 11i |
OCH3 | 8.14 ± 1.3 | — | — | — | — |
| para-azidophenyltropane 11l |
N3 | 2.12 ± 0.13 | — | — | — | — |
| para-trifluoromethylphenyltropane 11m |
CF3 | 13.1 ± 2.2 | — | — | — | — |
| para-acetylaminophenyltropane 11n |
NHCOCH3 | 64.2 ± 2.6 | — | — | — | — |
| para-propionylaminophenyltropane 11o |
NHCOC2H5 | 121 ± 2.7 | — | — | — | — |
| para-ethoxycarbonylaminophenyltropane 11p |
NHCO2C3H5 | 316 ± 48 | — | — | — | — |
| para-trimethylstannylphenyltropane 11q |
Sn(CH3)3 | 144 ± 37 | — | — | — | — |
| para-n-propylphenyltropane 11r |
n-C3H7 | 68.5 ± 7.1 | 70.4 ± 4.1 | 3920 ± 130 | 1.0 | 57.2 |
| para-isopropylphenyltropane 11s |
CH(CH3)2 | 597 ± 52 | 191 ± 9.5 | 75000 ± 5820 | 0.3 | 126 |
| para-vinylphenyltropane 11t |
CH-CH2 | 1.24 ± 0.2 | 9.5 ± 0.8 | 78 ± 4.1 | 7.7 | 62.9 |
| 11u | C(=CH2)CH3 | 14.4 ± 0.3 | 3.13 ± 0.16 | 1330 ± 333 | 0.2 | 92.4 |
| trans-3β-(4′-propenyl)phenyltropane 11v |
trans-CH=CHCH3 | 5.29 ± 0.53 | 11.4 ± 0.28 | 1590 ± 93 | 2.1 | 300 |
| para-allylphenyltropane 11x |
CH2CH=CH2 | 32.8 ± 3.1 | 28.4 ± 2.4 | 2480 ± 229 | 0.9 | 75.6 |
| para-alkynylphenyltropane[verification needed] 11y |
C≡CH | 1.2 ± 0.1 | 4.4 ± 0.4 | 83.2 ± 2.8 | 3.7 | 69.3 |
| para-propynylphenyltropane 11z |
C≡CCH3 | 2.37 ± 0.2 | 15.7 ± 1.5 | 820 ± 46 | 6.6 | 346 |
| para-phenylphenyltropane 11aa |
Ph | 10.3 ± 2.6f 29.4 ± 3.8ɑ |
— | — | — | — |
| 3β-2-naphthylphenyltropane 11bb |
3β-2-naphthyl | 3.32 ± 0.08f 3.53 ± 0.09ɑ |
— | — | — | — |
| para-methoxymethylphenyltropane 15 |
— | — | — | — | — |
- ɑKi value for displacement of [3H]DA uptake.
- bKi value for displacement of [3H]5-HT uptake.
- cKi value for displacement of [3H]NE uptake.
- d[3H]5-HT uptake to [3H]DA uptake ratio.
- e[3H]NE uptake to [3H]DA uptake ratio.
- fIC50 for displacement of [3H]cocaine.
- gValues from alternate data-set differing from that used in rest of table.
(3,4-Disubstituted phenyl)-tropanes
| Compound (+ S. Singh's name) |
X | Y | 2 Position | config | 8 | DA | 5-HT | NE |
| RTI-318 11bb |
β-naphthyl | CO2Me | β,β | NMe | 0.5 | 0.81 | 20 | |
| Dichloropane (RTI-111)[6] 17c |
Cl | Cl | CO2Me | β,β | NMe | 0.79 | 3.13 | 18.0 |
| RTI-88 [recheck] 17e |
NH2 | I | CO2Me | β,β | NMe | 1.35 | 1329 | 320 |
| RTI-97 17d |
NH2 | Br | CO2Me | β,β | NMe | 3.91 | 181 | 282 |
| RTI-112 17b |
Cl | Me | CO2Me | β,β | NMe | 0.82 | 10.5 | 36.2 |
| RTI-96 17a |
F | Me | CO2Me | β,β | NMe | 2.95 | 76 | 520 |
| RTI-295 | Et | I | CO2Me | β,β | NMe | 21.3 | 2.96 | 1349 |
| RTI-353 (EINT) | Et | I | CO2Me | β,β | NH | 331 | 0.69 | 148 |
| RTI-279 | Me | I | CO2Me | β,β | NH | 5.98 | 1.06 | 74.3 |
| RTI-280 | Me | I | CO2Me | β,β | NMe | 3.12 | 6.81 | 484 |
| Meltzer[7] | catechol | CO2Me | β,β | NMe | >100 | ? | ? | |
| Meltzer[7] | OAc | OAc | CO2Me | β,β | NMe | ? | ? | ? |
| Compound | Short Name (S. Singh) |
Y | X | DA | 5HT | NE | Selectivity 5-HTT/DAT |
Selectivity NET/DAT |
|---|---|---|---|---|---|---|---|---|
 | ||||||||
| 16a | F | H | 23 ± 7.8 | - | - | - | - | |
| 16b | Cl | H | 10.6 ± 1.8 | - | - | - | - | |
| 16c | Br | H | 7.93 ± 0.08ɑ | - | - | - | - | |
| 16d | I | H | 26.1 ± 1.7 | - | - | - | - | |
| meta-tributylstannylphenyltropane 16e |
SnBu3 | H | 1100 ± 170 | - | - | - | - | |
| 17a (RTI-96) |
CH3 | F | 2.95 ± 0.58 | - | - | - | - | |
| 17b (RTI-112) |
CH3 | Cl | 0.81 ± 0.05 | 10.5 ± 0.05 | 36.2 ± 1.0 | 13.0 | 44.7 | |
| 17c[6] (Dichloropane) (RTI-111) |
Cl | Cl | 0.79 ± 0.08 | 3.13 ± 0.36 | 18.0 ± 0.8 | 4.0 | 22.8 | |
| 17d (RTI-97) |
Br | NH2 | 3.91 ± 0.59 | 181 | 282 | - | - | |
| 17e (RTI-88) |
I | NH2 | 1.35 ± 0.11 | 120 ± 4 | 1329 ± 124 | 88.9 | 984 | |
| 17f | I | N3 | 4.93 ± 0.32 | - | - | - | - |
ɑIC50 determined in Cynomolgous monkey caudate-putamen
(3′,4′,5′-Trisubstituted para-methoxyphenyl)-tropanes
| Structure | Short Name (All compounds tested as HCl salts) |
X 3′-(meta) |
Y 5′-(di-meta) |
OR 4′-(para) |
DAT IC50 [3H](compound #)12 |
5-HTT Ki [3H]Paroxetine |
NET Ki [3H]Nisoxetine |
Selectivity NET/DAT Ratio Ki/IC50 |
Selectivity NET/5-HTT Ratio Ki/Ki |
|---|---|---|---|---|---|---|---|---|---|
| Cocaine | - | - | - | 89.1 | 95 | 1990 | 22 | 21 | |
| 6 | - | - | - | 0.82 ± 0.05 | 0.95 ± 0.04 | 21.8 ± 0.6 | 27 | 23 | |
 |
7a | H | H | CH3 | 6.5 ± 1.3 | 4.3 ± 0.5 | 1110 ± 64 | 171 | 258 |
 |
7b | H | H | C2H5 | 92 ± 8 | 1.7 ± 0.4 | 1690 ± 50 | 18 | 994 |
 |
7c | F | H | CH3 | 16 ± 1 | 4.8 ± 0.5 | 270 ± 50 | 17 | 56 |
 |
7d | Br | H | CH3 | 47 ± 15 | 3.1 ± 0.1 | 160 ± 20 | 3 | 52 |
 |
7f | Br | Br | CH3 | 92 ± 22 | 2.9 ± 0.1 | 4100 ± 400ɑ | 45 | 1413 |
 |
7e | I | H | CH3 | 170 ± 60 | 3.5 ± 0.4 | 180 ± 20 | 1 | 51 |
 |
7g | I | I | CH3 | 1300 ± 200 | 7.5 ± 0.8 | 180 ± 20 | 4 | 667 |
ɑN=2
2-Carbmethoxy modified (replaced/substituted)
| Structure | Short Name (All compounds tested as HCl salts) |
CO2R (2β-substituted) (compound 9 is 2β=R) |
DAT IC50 [3H](compound #)12 |
5-HTT Ki [3H]Paroxetine |
NET Ki [3H]Nisoxetine |
Selectivity NET/DAT Ratio Ki/IC50 |
Selectivity NET/5-HTT Ratio Ki/Ki |
|---|---|---|---|---|---|---|---|
|
7a | CH3 | 6.5 ± 1.3 | 4.3 ± 0.5 | 1110 ± 64 | 171 | 258 |
 |
8a | (CH3)2CH | 14 ± 3 | 135 ± 35 | 2010 ± 200 | 144 | 15 |
 |
8b | cyclopropane | 6.0 ± 2 | 29 ± 3 | 1230 ± 140 | 205 | 42 |
 |
8c | cyclobutane | 13 ± 3 | 100 ± 8 | >3000 | 231 | 30 |
 |
8d | O2N…1,4-xylene…(CH2)2 | 42 ± 8 | 2.9 ± 0.2 | 330 ± 20 | 8 | 114 |
 |
8e | H2N…1,4-xylene…(CH2)2 | 7.0 ± 2 | 8.3 ± 0.4 | 2200 ± 300ɑ | 314 | 265 |
 |
8f | CH3CONH…1,4-xylene…(CH2)2 | 6.0 ± 1 | 5.5 ± 0.5 | 1460 ± 30 | 243 | 265 |
 |
8g | H2N…2-bromo-1,4-dimethylbenzene…(CH2)2 | 3.3 ± 1.4 | 4.1 ± 0.6 | 1850 ± 90 | 561 | 451 |
 |
8h | H2N…1,3-dibromo-2,5-dimethylbenzene…(CH2)2 | 15 ± 6 | 2.0 ± 0.4 | 2710 ± 250ɑ | 181 | 1360 |
 |
8i | H2N…2-iodo-1,4-dimethylbenzene…(CH2)2 | 2.5 ± 0.7 | 3.5 ± 1 | 2040 ± 300ɑ | 816 | 583 |
 |
8j | H2N…1,3-diiodo-2,5-dimethylbenzene…(CH2)2 | 102 ± 15 | 1.0 ± 0.1 | 2600 ± 200ɑ | 25 | 2600 |
 |
9 | 3-(4-methylphenyl)-1,2-oxazole | 18 ± 6 | 860 ± 170 | >3000 | 167 | 3 |
ɑN=2
| Compound | Short Name (S. Singh) |
R | X | IC50 (nM) DAT [3H]WIN 35428 |
IC50 (nM) 5-HTT [3H]paroxetine |
IC50 (nM) NET [3H]nisoxetine |
Selectivity 5-HTT/DAT |
Selectivity NET/DAT |
|---|---|---|---|---|---|---|---|---|
 | ||||||||
| 23a | CH(CH3)2 | H | 85.1 ± 2.5 | 23121 ± 3976 | 32047 ± 1491 | 272 | 376 | |
| 23b | C6H5 | H | 76.7 ± 3.6 | 106149 ± 7256 | 19262 ± 593 | 1384 | 251 | |
| 24a | CH(CH3)2 | Cl | 1.4 ± 0.13 6.04 ± 0.31ɑ |
1400 ± 7 128 ± 15b |
778 ± 21 250 ± 0.9c |
1000 21.2d |
556 41.4e | |
| 24b | cyclopropyl | Cl | 0.96 ± 0.10 | 168 ± 1.8 | 235 ± 8.39 | 175 | 245 | |
| 24c | C6H5 | Cl | 1.99 ± 0.05 5.25 ± 0.76ɑ |
2340 ± 27 390 ± 34b |
2960 ± 220 242 ± 30c |
1176 74.3d |
1.3 41.6e | |
| 24d | C6H4-4-I | Cl | 32.6 ± 3.9 | 1227 ± 176 | 967.6 ± 26.3 | 37.6 | 29.7 | |
| 24e | C6H4-3-CH3 | Cl | 9.37 ± 0.52 | 2153 ± 143 | 2744 ± 140 | 230 | 293 | |
| 24f | C6H4-4-CH3 | Cl | 27.4 ± 1.5 | 1203 ± 42 | 1277 ± 118 | 43.9 | 46.6 | |
| 24g | C6H4-2-CH3 | Cl | 3.91 ± 0.23 | 3772 ± 384 | 4783 ± 387 | 965 | 1223 | |
| 24h | C6H4-4-Cl | Cl | 55 ± 2.3 | 16914 ± 1056 | 4883 ± 288 | 307 | 88.8 | |
| 24i | C6H4-4-OCH3 | Cl | 71 ± 5.6 | 19689 ± 1843 | 1522 ± 94 | 277 | 21.4 | |
| 24j | (CH2)2C6H4-4-NO2 | Cl | 2.71 ± 0.13 | - | - | - | - | |
| 24k | (CH)2C6H4-4-NH2 | Cl | 2.16 ± 0.25 | - | - | - | - | |
| 24l | (CH2)2C6H3-3-I-4-NH2 | Cl | 2.51 ± 0.25 | - | - | - | - | |
| 24m | (CH2)2C6H3-3-I-4-N3 | Cl | 14.5 ± 0.94 | - | - | - | - | |
| 24n | (CH2)2C6H4-4-N3 | Cl | 6.17 ± 0.57 | - | - | - | - | |
| 24o | (CH2)2C6H4-4-NCS | Cl | 5.3 ± 0.6 | - | - | - | - | |
| 24p | (CH2)2C6H4-4-NHCOCH2Br | Cl | 1.73 ± 0.06 | - | - | - | - | |
| 25a | CH(CH3)2 | I | 0.43 ± 0.05 2.79 ± 0.13ɑ |
66.8 ± 6.53 12.5 ± 1.0b |
285 ± 7.6 41.2 ± 3.0c |
155 4.5d |
663 14.8e | |
| 25b | cyclopropyl | I | 0.61 ± 0.08 | 15.5 ± 0.72 | 102 ± 11 | 25.4 | 167 | |
| 25c | C6H5 | I | 1.51 ± 0.34 6.85 ± 0.93ɑ |
184 ± 22 51.6 ± 6.2b |
3791 ± 149 32.7 ± 4.4c |
122 7.5d |
2510 4.8e | |
| 26a | CH(CH3)2 | CH3 | 6.45 ± 0.85 15.3 ± 2.08ɑ |
6090 ± 488 917 ± 54b |
1926 ± 38 73.4 ± 11.6c |
944 59.9d |
299 4.8e | |
| 26b | CH(C2H5)2 | CH3 | 19.1 ± 1 | 4499 ± 557 | 3444 ± 44 | 235 | 180 | |
| 26c | cyclopropyl | CH3 | 17.8 ± 0.76 | 485 ± 21 | 2628 ± 252 | 27.2 | 148 | |
| 26d | cyclobutyl | CH3 | 3.74 ± 0.52 | 2019 ± 133 | 4738 ± 322 | 540 | 1267 | |
| 26e | cyclopentyl | CH3 | 1.68 ± 0.14 | 1066 ± 109 | 644 ± 28 | 634 | 383 | |
| 26f | C6H5 | CH3 | 3.27 ± 0.06 9.13 ± 0.79ɑ |
24500 ± 1526 1537 ± 101b |
5830 ± 370 277 ± 23c |
7492 168d |
1783 30.3e | |
| 26g | C6H4-3-CH3 | CH3 | 8.19 ± 0.90 | 5237 ± 453 | 2136 ± 208 | 639 | 261 | |
| 26h | C6H4-4-CH3 | CH3 | 81.2 ± 16 | 15954 ± 614 | 4096 ± 121 | 196 | 50.4 | |
| 26i | C6H4-2-CH3 | CH3 | 23.2 ± 0.97 | 11040 ± 504 | 25695 ± 1394 | 476 | 1107 | |
| 26j | C6H4-4-Cl | CH3 | 117 ± 7.9 | 42761 ± 2399 | 9519 ± 864 | 365 | 81.3 | |
| 26k | C6H4-4-OCH3 | CH3 | 95.6 ± 8.8 | 82316 ± 7852 | 3151 ± 282 | 861 | 33.0 |
- ɑKi value for displacement of [3H]DA uptake.
- bKi value for displacement of [3H]5-HT uptake.
- cKi value for displacement of [3H]NE uptake.
- d[3H]5-HT uptake to [3H]DA uptake ratio.
- e[3H]NE uptake to [3H]DA uptake ratio.
Carboxyaryl
| Compound | X | 2 Position | config | 8 | DA | 5-HT | NE |
| RTI-122 | I | -CO2Ph | β,β | NMe | 1.50 | 184 | 3,791 |
| RTI-113 | Cl | -CO2Ph | β,β | NMe | 1.98 | 2,336 | 2,955 |
| RTI-277 | NO2 | -CO2Ph | β,β | NMe | 5.94 | 2,910 | 5,695 |
| RTI-120 [recheck] | Me | -CO2Ph | β,β | NMe | 3.26 | 24,471 | 5,833 |
| RTI-116 | Cl | -CO2(p-C6H4I) | β,β | NMe | 33 | 1,227 | 968 |
| RTI-203 | Cl | CO2(m-C6H4Me) | β,β | NMe | 9.37 | 2153 | 2744 |
| RTI-204 | Cl | -CO2(o-C6H4Me) | β,β | NMe | 3.91 | 3,772 | 4,783 |
| RTI-205 | Me | -CO2(m-C6H4Me) | β,β | NMe | 8.19 | 5,237 | 2,137 |
| RTI-206 | Cl | -CO2(p-C6H4Me) | β,β | NMe | 27.4 | 1,203 | 1,278 |
Carboxyalkyl
| Code | X | 2 Position | config | 8 | DA | 5-HT | NE |
| RTI-77 | Cl | CH2C2(3-iodo-p-anilino) | β,β | NMe | 2.51 | — | 2247 |
| RTI-121 | I | -CO2Pri | β,β | NMe | 0.43 | 66.8 | 285 |
| RTI-153 | I | -CO2Pri | β,β | NH | 1.06 | 3.59 | 132 |
| RTI-191 | I | -CO2Prcyc | β,β | NMe | 0.61 | 15.5 | 102 |
| RTI-114 | Cl | -CO2Pri | β,β | NMe | 1.40 | 1,404 | 778 |
| RTI-278 | NO2 | -CO2Pri | β,β | NMe | 8.14 | 2,147 | 4,095 |
| RTI-190 | Cl | -CO2Prcyc | β,β | NMe | 0.96 | 168 | 235 |
| RTI-193 | Me | -CO2Prcyc | β,β | NMe | 1.68 | 1,066 | 644 |
| RTI-117 | Me | -CO2Pri | β,β | NMe | 6.45 | 6,090 | 1,926 |
| RTI-150 | Me | -CO2Bucyc | β,β | NMe | 3.74 | 2,020 | 4,738 |
| RTI-127 | Me | -CO2C(H)Et2 | β,β | NMe | 19 | 4500 | 3444 |
| RTI-338 | ethyl | -CO2C2Ph | β,β | NMe | 1104 | 7.41 | 3366 |
Use of a cyclopropyl ester appears to enable better MAT retention than does the choice of isopropyl ester.
Use of a cycBu resulted in greater DAT selectivity than did the cycPr homologue.
Carboxamides
| Code (S. Singh #) |
X | 2 Position | config | 8 | DA [3H]WIN 35428 (IC50 nM) |
NE [3H]nisoxetine |
5-HT [3H]paroxetine (IC50 nM) |
Selectivity 5-HTT/DAT |
Selectivity NET/DAT |
| RTI-106 27b |
Cl | CON(H)Me | β,β | NMe | 12.4 ± 1.17 | 1584 ± 62 | 1313 ± 46 | 106 | 128 |
| RTI-118 27a |
Cl | CONH2 | β,β | NMe | 11.5 ± 1.6 | 4270 ± 359 | 1621 ± 110 | 141 | 371 |
| RTI-222 29d |
Me | morpholinyl | β,β | NMe | 11.7 ± 0.87 | 23601 ± 1156 | >100K | >8547 | 2017 |
| RTI-129 27e |
Cl | CONMe2 | β,β | NMe | 1.38 ± 0.1 | 942 ± 48 | 1079 ± 102 | 792 | 683 |
| RTI-146 27d |
Cl | CONHCH2OH | β,β | NMe | 2.05 ± 0.23 | 144 ± 3 | 97.8 ± 10 | 47.7 | 70.2 |
| RTI-147 27i |
Cl | CON(CH2)4 | β,β | NMe | 1.38 ± 0.03 | 3,950 ± 72 | 12400 ± 1207 | 8985 | 2862 |
| RTI-156 | Cl | CON(CH2)5 | β,β | NMe | 6.61 | 5832 | 3468 | ||
| RTI-170 | Cl | CON(H)CH2C≡CH | β,β | NMe | 16.5 | 1839 | 4827 | ||
| RTI-172 | Cl | CON(H)NH2 | β,β | NMe | 44.1 | 3914 | 3815 | ||
| RTI-174 | Cl | CONHCOMe | β,β | NMe | 158 | >43K | >125K | ||
| RTI-182 | Cl | CONHCH2COPh | β,β | NMe | 7.79 | 1722 | 827 | ||
| RTI-183✲ 27g |
Cl | CON(OMe)Me | β,β | NMe | 0.85 ± 0.06 | 549 ± 18.5 | 724 ± 94 | 852 | 646 |
| RTI-186 29c |
Me | CON(OMe)Me | β,β | NMe | 2.55 ± 0.43 | 422 ± 26 | 3402 ± 353 | 1334 | 165 |
| RTI-198 27h |
Cl | CON(CH2)3 | β,β | NMe | 6.57 ± 0.67 | 990 ± 4.8 | 814 ± 57 | 124 | 151 |
| RTI-196 27c |
Cl | CONHOMe | β,β | NMe | 10.7 ± 1.25 | 9907 ± 632 | 43700 ± 1960 | 4084 | 926 |
| RTI-201 | Cl | CONHNHCOPh | β,β | NMe | 91.8 | >20K | >48K | ||
| RTI-208 27j |
Cl | CONO(CH2)3 | β,β | NMe | 1.47 ± 0.13 | 1083 ± 76 | 2470 ± 56 | 1680 | 737 |
| RTI-214 27l |
Cl | CON(-CH2CH2-)2O | β,β | NMe | 2.90 ± 0.3 | 8545 ± 206 | 88769 ± 1855 | 30610 | 2946 |
| RTI-215 27f |
Cl | CONEt2 | β,β | NMe | 5.48 ± 0.19 | 5532 ± 299 | 9433 ± 770 | 1721 | 1009 |
| RTI-217 | Cl | CONH(m-C6H4OH) | β,β | NMe | 4.78 | >30K | >16K | ||
| RTI-218✲ | Cl | CON(Me)OMe | β,β | NMe | 1.19 | 520 | 1911 | ||
| RTI-226 27m |
Cl | CONMePh | β,β | NMe | 45.5 ± 3 | 2202 ± 495 | 23610 ± 2128 | 519 | 48.4 |
| RTI-227 | I | CONO(CH2)3 | β,β | NMe | 0.75 | 446 | 230 | ||
| RTI-229[10] 28a |
I | CON(CH2)4 | β,β | NMe | 0.37 ± 0.04 | 991 ± 21 | 1728 ± 39 | 4670 | 2678 |
| 27k | 6.95 ± 1.21 | 1752 ± 202 | 3470 ± 226 | 499 | 252 | ||||
| 28b | 1.08 ± 0.15 | 103 ± 6.2 | 73.9 ± 8.1 | 68.4 | 95.4 | ||||
| 28c | 0.75 ± 0.02 | 357 ± 42 | 130 ± 15.8 | 173 | 476 | ||||
| 29a | 41.8 ± 2.45 | 4398 ± 271 | 6371 ± 374 | 152 | 105 | ||||
| 29b | 24.7 ± 1.93 | 6222 ± 729 | 33928 ± 2192 | 1374 | 252 |
✲RTI-183 and RTI-218 suggest possible copy-error, seeing as "CON(OMe)Me" & "CON(Me)OMe" difference between methyl & methoxy render as the same.
| Compound | Short Name (S. Singh) |
R | X | IC50 (nM) DAT [3H]WIN 35428 |
IC50 (nM) 5-HTT [3H]Paroxetine |
IC50 (nM) NET [3H]Nisoxetine |
Selectivity 5-HTT/DAT |
Selectivity NET/DAT |
|---|---|---|---|---|---|---|---|---|
| 29a | NH2 | CH3 | 41.8 ± 2.45 | 6371 ± 374 | 4398 ± 271 | 152 | 105 | |
| 29b | N(CH2CH3)2 | CH3 | 24.7 ± 1.93 | 33928 ± 2192 | 6222 ± 729 | 1374 | 252 | |
| 29c | N(OCH3)CH3 | CH3 | 2.55 ± 0.43 | 3402 ± 353 | 422 ± 26 | 1334 | 165 | |
| 29d | 4-morpholine | CH3 | 11.7 ± 0.87 | >100000 | 23601 ± 1156 | >8547 | 2017 |
Heterocycles
These heterocycles are sometimes referred to as the "bioisosteric equivalent" of the simpler esters from which they are derived. A potential disadvantage of leaving the ββ-ester unreacted is that in addition to being hydrolyzable, it can also epimerize[11] to the energetically more favorable trans configuration. This can happen to cocaine also.
(compound model 34)
Several of the oxadiazoles contain the same number and types of heteroatoms, while their respective binding potencies display 8×-15× difference. A finding that would not be accounted for by their affinity originating from hydrogen bonding.
To explore the possibility of electrostatic interactions, the use of molecular electrostatic potentials (MEP) were employed with model compound 34 (replacing the phenyltropane moiety with a methyl group). Focusing on the vicinity of the atoms @ positions A—C, the minima of electrostatic potential near atom position A (ΔVmin(A)), calculated with semi-empirical (AM1) quantum mechanics computations (superimposing the heterocyclic and phenyl rings to ascertain the least in the way of steric and conformational discrepancies) found a correlation between affinity @ DAT and ΔVmin(A): wherein the values for the latter for 32c = 0, 32g = -4, 32h = -50 & 32i = -63 kcal/mol.
In contrast to this trend, it is understood that an increasingly negative ΔVmin is correlated with an increase of strength in hydrogen bonding, which is the opposing trend for the above; this indicates that the 2β-substituents (at least for the heterocyclic class) are dominated by electrostatic factors for binding in-the-stead of the presumptive hydrogen bonding model for this substituent of the cocaine-like binding ligand.[c]
3-Substituted-isoxazol-5-yl
| Code (S.S. #) |
X | R | DA | NE | 5HT |
|---|---|---|---|---|---|
| RTI-165 | Cl | 3-methylisoxazol-5-yl | 0.59 | 181 | 572 |
| RTI-171 | Me | 3-methylisoxazol-5-yl | 0.93 | 254 | 3818 |
| RTI-180 | I | 3-methylisoxazol-5-yl | 0.73 | 67.9 | 36.4 |
| RTI-177 32g |
Cl | 3-phenylisoxazol-5-yl | 1.28 ± 0.18 | 504 ± 29 | 2420 ± 136 |
| RTI-176 | Me | 3-phenylisoxazol-5-yl | 1.58 | 398 | 5110 |
| RTI-181 | I | 3-phenylisoxazol-5-yl | 2.57 | 868 | 100 |
| RTI-184 | H | methyl | 43.3 | — | 6208 |
| RTI-185 | H | Ph | 285 | — | >12K |
| RTI-334 | Cl | 3-ethylisoxazol-5-yl | 0.50 | 120 | 3086 |
| RTI-335 | Cl | isopropyl | 1.19 | 954 | 2318 |
| RTI-336 | Cl | 3-(4-methylphenyl)isoxazol-5-yl | 4.09 | 1714 | 5741 |
| RTI-337 | Cl | 3-t-butyl-isoxazol-5-yl | 7.31 | 6321 | 37K |
| RTI-345 | Cl | p-chlorophenyl | 6.42 | 5290 | >76K |
| RTI-346 | Cl | p-anisyl | 1.57 | 762 | 5880 |
| RTI-347 | Cl | p-fluorophenyl | 1.86 | 918 | 7257 |
| RTI-354 | Me | 3-ethylisoxazol-5-yl | 1.62 | 299 | 6400 |
| RTI-366 | Me | R = isopropyl | 4.5 | 2523 (1550) | 42,900 (3900) |
| RTI-371 | Me | p-chlorophenyl | 8.74 | >100K (60,200) | >100K (9090) |
| RTI-386 | Me | p-anisyl | 3.93 | 756 (450) | 4027 (380) |
| RTI-387 | Me | p-fluorophenyl | 6.45 | 917 (546) | >100K (9400) |
3-Substituted-1,2,4-oxadiazole
| Code (Singh's #) |
X | R | DAT (IC50 nM) displacement of [H3]WIN 35428 |
NET (IC50 nM) [H3]nisoxetine |
5-HTT (IC50 nM) [H3]paroxetine |
Selectivity 5-HTT/DAT |
Selectivity NET/DAT |
|---|---|---|---|---|---|---|---|
| ααRTI-87 | H | 3-methyl-1,2,4-oxadiazole | 204 | 36K | 30K | ||
| βαRTI-119 | H | 3-methyl-1,2,4-oxadiazole | 167 | 7K | 41K | ||
| αβRTI-124 | H | 3-methyl-1,2,4-oxadiazole | 1028 | 71K | 33K | ||
| RTI-125 (32a) |
Cl | 3-methyl-1,2,4-oxadiazole | 4.05 ± 0.57 | 363 ± 36 | 2584 ± 800 | 637 | 89.6 |
| ββRTI-126[12] (31) |
H | 3-methyl-1,2,4-oxadiazole | 100 ± 6 | 7876 ± 551 | 3824 ± 420 | 38.3 | 788 |
| RTI-130 (32c) |
Cl | 3-phenyl-1,2,4-oxadiazole | 1.62 ± 0.02 | 245 ± 13 | 195 ± 5 | 120 | 151 |
| RTI-141 (32d) |
Cl | 3-(p-anisyl)-1,2,4-oxadiazole | 1.81 ± 0.19 | 835 ± 8 | 337 ± 40 | 186 | 461 |
| RTI-143 (32e) |
Cl | 3-(p-chlorophenyl)-1,2,4-oxadiazole | 4.06 ± 0.22 | 40270 ± 180 (4069) |
404 ± 56 | 99.5 | 9919 |
| RTI-144 (32f) |
Cl | 3-(p-bromophenyl)-1,2,4-oxadiazole | 3.44 ± 0.36 | 1825 ± 170 | 106 ± 10 | 30.8 | 532 |
| βRTI-151 (33) |
Me | 3-phenyl-1,2,4-oxadiazole | 2.33 ± 0.26 | 60 ± 2 | 1074 ± 130 | 459 | 25.7 |
| αRTI-152 | Me | 3-phenyl-1,2,4-oxadiazole | 494 | — | 1995 | ||
| RTI-154 (32b) |
Cl | 3-isopropyl-1,2,4-oxadiazole | 6.00 ± 0.55 | 135 ± 13 | 3460 ± 250 | 577 | 22.5 |
| RTI-155 | Cl | 3-cyclopropyl-1,2,4-oxadiazole | 3.41 | 177 | 4362 |
| Code | X | 2 Group | DAT (IC50 nM) displacement of [H3]WIN 35428 |
NET (IC50 nM) displacement of [H3]nisoxetine |
5-HTT (IC50 nM) displacement of [H3]paroxetine |
Selectivity 5-HTT/DAT |
Selectivity NET/DAT |
|---|---|---|---|---|---|---|---|
| RTI-157 | Me | tetrazole | 1557 | >37K | >43K | ||
| RTI-163 | Cl | tetrazole | 911 | — | 5456 | ||
| RTI-178 | Me | 5-phenyl-oxazol-2-yl | 35.4 | 677 | 1699 | ||
| RTI-188 | Cl | 5-phenyl-1,3,4-oxadiazol-2-yl | 12.6 | 930 | 3304 | ||
| RTI-189 (32i) |
Cl | 5-phenyl-oxazol-2-yl | 19.7 ± 1.98 | 496 ± 42 | 1120 ± 107 | 56.8 | 25.5 |
| RTI-194 | Me | 5-methyl-1,3,4-oxadiazol-2-yl | 4.45 | 253 | 4885 | ||
| RTI-195 | Me | 5-phenyl-1,3,4-oxadiazol-2-yl | 47.5 | 1310 | >22,000 | ||
| RTI-199 | Me | 5-phenyl-1,3,4-thiadiazol-2-yl | 35.9 | >24,000 | >51,000 | ||
| RTI-200 | Cl | 5-phenyl-1,3,4-thiadiazol-2-yl | 15.3 | 4142 | >18,000 | ||
| RTI-202 | Cl | benzothiazol-2-yl | 1.37 | 403 | 1119 | ||
| RTI-219 | Cl | 5-phenylthiazol-2-yl | 5.71 | 8516 | 10,342 | ||
| RTI-262 | Cl | ||||||
| RTI-370 | Me | 3-(p-cresyl)isoxazol-5-yl | 8.74 | 6980 | >100K | ||
| RTI-371 | Cl | 3-(p-chlorophenyl)isoxazol-5-yl | 13 | >100K | >100K | ||
| RTI-436 | Me | -CH=CHPh[14] | 3.09 | 1960 (1181) | 335 (31) | ||
| RTI-470 | Cl | o-Cl-benzothiazol-2-yl | 0.094 | 1590 (994) | 1080 (98) | ||
| RTI-451 | Me | benzothiazol-2-yl | 1.53 | 476 (287) | 7120 (647) | ||
| 32g | 1.28 ± 0.18 | 504 ± 29 | 2420 ± 136 | 1891 | 394 | ||
| 32h | 12.6 ± 10.3 | 929 ± 88 | 330 ± 196 | 262 | 73.7 |
N.B There are some alternative ways of making the tetrazole ring however; C.f. the sartan drugs synthesis schemes. Bu3SnN3 is a milder choice of reagent than hydrogen azide (c.f. Irbesartan).
2-Alkyl Esters & Ethers
| Short Name (S. Singh) |
2β=R | Ki (nM) DAT [3H]WIN 35428 |
IC50 (nM) [3H]DA uptake |
Selectivity uptake/binding |
|---|---|---|---|---|
| 59a | CH=CHCO2CH3 | 22 ± 2 | 123 ± 65 | 5.6 |
| 59b | CH2CH2CO2CH3 | 23 ± 2 | 166 ± 68 | 7.2 |
| 59c | (CH2)2CH=CHCO2CH3 | 20 ± 2 | 203 ± 77 | 10.1 |
| 59d | (CH22)4CO2CH3 | 30 ± 2 | 130 ± 7 | 4.3 |
| 59e | CH=CHCH2OH | 26 ± 3 | 159 ± 43 | 6.1 |
| 59f | CH2CH2CH2OH | 11 ± 1 | 64 ± 32 | 5.8 |
| 59g | CH2CH2COC6H5 | 28 ± 2 | 47 ± 15 | 1.7 |
| Short Name (S. Singh) |
Stereochemistry | DAT [3H]WIN 35428 IC50 (nM) |
5-HTT [3H]Paroxetine IC50 (nM) |
NET [3H]Nisoxetine IC50 (nM) |
Selectivity 5-HTT/DAT |
Selectivity NET/DAT |
|---|---|---|---|---|---|---|
| Paroxetine | 623 ± 25 | 0.28 ± 0.02 | 535 ± 15 | 0.0004 | 0.8 | |
| R-60a | 2β,3β | 308 ± 20 | 294 ± 18 | 5300 ± 450 | 0.9 | 17.2 |
| R-60b | 2α,3β | 172 ± 8.8 | 52.9 ± 3.6 | 26600 ± 1200 | 0.3 | 155 |
| R-60c | 2β,3α | 3.01 ± 0.2 | 42.2 ± 16 | 123 ± 9.5 | 14.1 | 40.9 |
| S-60d | 2β,3β | 1050 ± 45 | 88.1 ± 2.8 | 27600 ± 1100 | 0.08 | 26.3 |
| S-60e | 2α,3β | 1500 ± 74 | 447 ± 47 | 2916 ± 1950 | 0.3 | 1.9 |
| S-60f | 2β,3α | 298 ± 17 | 178 ± 13 | 12400 ± 720 | 0.6 | 41.6 |
Acyl (C2-propanoyl)
| # (#) |
X | Y | 2 Position | config | 8 | DA | 5-HT | NE |
| WF-23 (39n) |
β-naphthyl | C(O)Et | β,β | NMe | 0.115 | 0.394 | No data | |
| WF-31 | -Pri | H | C.O.Et | β,β | NMe | 615 | 54.5 | No data |
| WF-11✲ (39e) |
Me | H | -C.O.Et | β,β | NMe | 8.2 | 131 | No data |
| WF-25 (39a) |
H | H | -C.O.Et | β,β | NMe | 48.3 | 1005 | No data |
| WF-33 | 6-MeoBN | C(O)Et | α,β | NMe | 0.13 | 2.24 | No data | |
| ✲Compound WF-11 has been shown, under consistent exposure, to elicit a biological response opposite of cocaine i.e. tyrosine hydroxylase gene expression down-regulation (instead of up-regulation as has been observed to be the case for chronic cocaine administration) | ||||||||
| S. Singh's alphanumeric assignation (name) |
R1 | R2 | DAT
[125I]RTI-55 IC50 (nM) |
5-HTT
[3H]Paroxetine Ki (nM) |
Selectivity
5-HTT/DAT |
|---|---|---|---|---|---|
| cocaine | 173 ± 19 | — | — | ||
| Troparil 11a (WIN 35065-2) |
98.8 ± 12.2 | — | — | ||
| WF-25 39a |
C2H5 | C6H5 | 48.3 ± 2.8 | 1005 ± 112 | 20.8 |
| 39b | CH3 | C6H5 | 114 ± 22 | 1364 ± 616 | 12.0 |
| 39c | C2H5 | C6H4-4-F | 15.3 ± 2.8 | 630 ± 67 | 41.2 |
| 39d | CH3 | C6H4-4-F | 70.8 ± 13 | 857 ± 187 | 12.1 |
| WF-11 39e |
C2H5 | C6H4-4-CH3 | 8.2 ± 1.6 | 131 ± 1 | 16.0 |
| (+)-39e | C2H5 | C6H4-4-CH3 | 4.21 ± 0.05 | 74 ± 12 | 17.6 |
| (-)-39e | C2H5 | C6H4-4-CH3 | 1337 ± 122 | >10000 | — |
| 39f | CH3 | C6H4-4-CH3 | 9.8 ± 0.5 | 122 ± 22 | 12.4 |
| 39g | CH3 | C6H4-4-C2H5 | 152 ± 24 | 78.2 ± 22 | 0.5 |
| 39h | C2H5 | C6H4-4-CH(CH3)2 | 436 ± 41 | 35.8 ± 4.4 | 0.08 |
| 39i | C2H5 | C6H4-4-C(CH3)3 | 2120 ± 630 | 1771 ± 474 | 0.8 |
| 39j | C2H5 | C6H4-4-C6H5 | 2.29 ± 1.08 | 4.31 ± 0.01 | 1.9 |
| 39k | C2H5 | C6H4-2-CH3 | 1287 ± 322 | 710000 | >7.8 |
| 39l | C2H5 | 1-naphthyl | 5.43 ± 1.27 | 20.9 ± 2.9 | 3.8 |
| 39m | CH3 | 1-naphthyl | 10.1 ± 2.2 | 25.6 ± 5.1 | 2.5 |
| WF-23 39n |
C2H5 | 2-naphthyl | 0.115 ± 0.021 | 0.394 ± 0.074 | 3.5 |
| 39o | CH3 | 2-naphthyl | 0.28 ± 0.11 | 1.06 ± 0.36 | 3.8 |
| 39p | C2H5 | C6H4-4-CH(C2H5)2 | 270 ± 38 | 540 ± 51 | 2.0 |
| 39q | C2H5 | C6H4-4-C6H11 | 320 ± 55 | 97 ± 12 | 0.30 |
| 39r | C2H5 | C6H4-4-CH=CH2 | 0.90 ± 0.34 | 3.2 ± 1.3 | 3.5 |
| 39s | C2H5 | C6H4-4-C(=CH2)CH3 | 7.2 ± 2.1 | 0.82 ± 0.38 | 0.1 |
Ester reduction
Note: p-fluorophenyl is weaker than the others. RTI-145 is not peroxy, it is a methyl carbonate.
| Code | X | 2 Position | config | 8 | DA | 5-HT | NE |
| RTI-100 | F | -CH2OH | β,β | NMe | 47 | 4741 | no data |
| RTI-101 | I | -CH2OH | β,β | NMe | 2.2 | 26 | no data |
| RTI-99 | Br | -CH2OH | β,β | NMe | 1.49 | 51 | no data |
| RTI-93 | Cl | -CH2OH | β,β | NMe | 1.53 | 204 | 43.8 |
| RTI-105 | Cl | -CH2OAc | β,β | NMe | 1.60 | 143 | 127 |
| RTI-123 | Cl | -CH2OBz | β,β | NMe | 1.78 | 3.53 | 393 |
| RTI-145 | Cl | -CH2OCO2Me | β,β | NMe | 9.60 | 2.93 | 1.48 |
2-Phenyl-3-Phenyltropanes
| Short Name (S. Singh) |
Stereochemistry | X (para) |
DAT [3H]WIN 35428 IC50 (nM) |
DAT [3H]Mazindol Ki (nM) |
5-HTT [3H]Paroxetine IC50 (nM) |
[3H]DA uptake Ki (nM) | [3H]5-HT uptake Ki (nM) | Selectivity [3H]5-HT/[3H]DA |
|---|---|---|---|---|---|---|---|---|
| Cocaine | (2β,3β) | (H) | 89 ± 4.8 | 281 | 1050 ± 89 | 423 | 155 | 0.4 |
| 67a | 2β,3β | H | 12.6 ± 1.8 | 14.9 | 21000 ± 3320 | 28.9 | 1100 | 38.1 |
| 67b | 2β,3α | H | - | 13.8 | - | 11.7 | 753 | 64.3 |
| 67c | 2α,3α | H | 690 ± 37 | - | 41300 ± 5300 | - | - | - |
| 68 | 2β,3α | F | - | 6.00 | - | 4.58 | 122 | 26.6 |
| 69a | 2β,3β | CH3 | 1.96 ± 0.08 | 2.58 | 11000 ± 83 | 2.87 | 73.8 | 25.7 |
| 69b | 2β,3α | CH3 | - | 2.87 | - | 4.16 | 287 | 69.0 |
| 69c | 2α,3α | CH3 | 429 ± 59 | - | 15800 ± 3740 | - | - | - |
2-Alkane/Alkene
| Structure | Singh's # | R | X | DAT mazindol displacement |
DA uptake | 5-HT Uptake | Selectivity DA uptake/DAT binding |
|---|---|---|---|---|---|---|---|
|
11a WIN 35062-2 |
89.4 | 53.7 | 186 | 0.6 | ||
|
11c | 0.83 ± 00.7 | 28.5 ± 0.9 | — | 34.3 | ||
|
11f | 5.76 | 6.92 | 23.2 | 1.2 | ||
 |
41a | (CH2)2CH3 | H | 12.2 | 6.89 | 86.8 | 0.6 |
 |
41b | (CH2)3C6H5 | H | 16 ± 2a | 43 ± 13b | — | 2.7 |
 |
42 | (CH2)2CH3 | F | 5.28 | 1.99 | 21.7 | 0.4 |
 |
43a | CH=CH2 | Cl | 0.59 ± 0.15 | 2.47 ± 0.5 | — | 4.2 |
 |
43b | E-CH=CHCl | Cl | 0.42 ± 0.04 | 1.13 ± 0.27 | — | 2.7 |
 |
43c | Z-CH=CHCl | Cl | 0.22 ± 0.02 | 0.88 ± 0.05 | — | 4.0 |
 |
43d | E-CH=CHC6H5 | Cl | 0.31 ± 0.04 | 0.66 ± 0.01 | — | 2.1 |
 |
43e | Z-CH=CHC6H5 | Cl | 0.14 ± 0.07 | 0.31 ± 0.09 | — | 2.2 |
 |
43f | CH2CH3 | Cl | 2.17 ± 0.20 | 2.35 ± 0.52 | — | 1.1 |
 |
43g | (CH2)2CH3 | Cl | 0.94 ± 0.08 | 1.08 ± 0.05 | — | 1.1 |
 |
43h | (CH2)3CH3 | Cl | 1.21 ± 0.18 | 0.84 ± 0.05 | — | 0.7 |
 |
43i | (CH2)5CH3 | Cl | 156 ± 15 | 271 ± 3 | — | 1.7 |
 |
43j | (CH2)2C6H5 | Cl | 1.43 ± 0.03 | 1.54 ± 0.08 | — | 1.0 |
 |
44a | (CH2)2CH3 | CH3 | 1.57 | 1.10 | 10.3 | 0.7 |
 |
44b | (CH2)3CH3 | CH3 | 1.82 | 1.31 | 15.1 | 0.7 |
 |
45 | (CH2)2CH3 | H | 74.9 | 30.2 | 389 | 0.4 |
 |
46 | (CH2)2CH3 | F | 21.1 | 12.1 | 99.6 | 0.6 |
 |
47a | (CH2)2CH3 | CH3 | 8.91 | 11.8 | 50.1 | 1.3 |
 |
47b | (CH2)3CH3 | CH3 | 11.4 | 10.1 | 51.0 | 0.9 |
aKi value for displacement of WIN 35428.
bIC50 value.
Irreversible covalent (cf. ionic) C2 ligands
Irreversible (phenylisothiocyanate) binding ligand (Murthy, V.; Martin, T. J.; Kim, S.; Davies, H. M. L.; Childers, S. R. (2008). "In Vivo Characterization of a Novel Phenylisothiocyanate Tropane Analog at Monoamine Transporters in Rat Brain". Journal of Pharmacology and Experimental Therapeutics. 326 (2): 587–595. doi:10.1124/jpet.108.138842. PMID 18492949.)[15] RTI-76:[16] 4′-isothiocyanatophenyl (1R,2S,3S,5S)-3-(4-chlorophenyl)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate. Also known as: 3β-(p-chlorophenyl)tropan-2β-carboxylic acid p-isothiocyanatophenylmethyl ester.
Note the contrast to the phenylisothiocyanate covalent binding site location as compared to the one on p-Isococ, a non-phenyltropane cocaine analogue.
Benztropine based (C2-position hetero-substituted)
F&B series (Biotin side-chains etc.)
One patent claims a series of compounds with biotin-related sidechains are pesticides.[12]
| Code | para-X | C2-Tropane Position | config | DA | NE | 5-HT |
| RTI-224 | Me | F1c | β,β | 4.49 | — | 155.6 |
| RTI-233 | Me | F2 | β,β | 4.38 | 516 | 73.6 |
| RTI-235 | Me | F3 d | β,β | 1.75 | 402 | 72.4 |
| RTI-236 | Me | B1 d | β,β | 1.63 | 86.8 | 138 |
| RTI-237 | Me | B2 d | β,β | 7.27 | 258 | 363 |
| RTI-244 | Me | B3 d | β,β | 15.6 | 1809 | 33.7 |
| RTI-245 | Cl | F4 c | β,β | 77.3 | — | — |
| RTI-246 | Me | F4 c | β,β | 50.3 | 3000 | — |
| RTI-248 | Cl | F6 c | β,β | 9.73 | 4674 | 6.96 |
| RTI-249 | Cl | F1 c | β,β | 8.32 | 5023 | 81.6 |
| RTI-266 | Me | F2 | β,β | 4.80 | 836 | 842 |
| RTI-267 | Me | F7 wrong | β,β | 2.52 | 324 | 455 |
| RTI-268 | Me | F7 right | β,β | 3.89 | 1014 | 382 |
| RTI-269 | Me | F8 | β,β | 5.55 | 788 | 986 |
Miscellany (i.e. Misc./Miscellaneous) C2-substituents
| Code | X | 2 Position | config | 8 | DA | 5-HT | NE |
| RTI-102 | I | CO2H | β,β | NMe | 474 | 1928 | 43,400 |
| RTI-103 | Br | CO2H | β,β | NMe | 278 | 3070 | 17,400 |
| RTI-104 | F | CO2H | β,β | NMe | 2744 | >100K | >100K |
| RTI-108 | Cl | -CH2Cl | β,β | NMe | 2.64 | 98 | 129.8 |
| RTI-241 | Me | -CH2CO2Me | β,β | NMe | 1.02 | 619 | 124 |
| RTI-139 | Cl | -CH3 | β,β | NMe | 1.67 | 85 | 57 |
| RTI-161 | Cl | -C≡N | β,β | NMe | 13.1 | 1887 | 2516 |
| RTI-230 | Cl | H3C–C=CH2 | β,β | NMe | 1.28 | 57 | 141 |
| RTI-240 | Cl | -CHMe2 | β,β | NMe | 1.38 | 38.4 | 84.5 |
| RTI-145 | Cl | -CH2OCO2Me | β,β | NMe | 9.60 | 2,932 | 1,478 |
| RTI-158 | Me | -C≡N | β,β | NMe | 57 | 5095 | 1624 |
| RTI-131 | Me | -CH2NH2 | β,β | NMe | 10.5 | 855 | 120 |
| RTI-164 | Me | -CH2NHMe | β,β | NMe | 13.6 | 2246 | 280 |
| RTI-132 | Me | -CH2NMe2 | β,β | NMe | 3.48 | 206 | 137 |
| RTI-239 | Me | -CHMe2 | β,β | NMe | 0.61 | 114 | 35.6 |
| RTI-338 | Et | -CO2CH2Ph | β,β | NMe | 1104 | 7.41 | 3366 |
| RTI-348 | H | -Ph | β,β | NMe | 28.2 | >34,000 | 2670 |
C2-truncated (non-ecgonine w/o 2-position-replacement tropanes)
Aryl-Tropenes
| Test compound | DA-uptake IC50(μM) | NA-uptake IC50(μM) | 5-HT-uptake IC50(μM) |
| (+)-3-(4-Chlorophenyl)-8-H-aza-bicyclo[3.2.1]oct-2-ene | 0.26 | 0.028 | 0.010 |
| (+)-3-Napthalen-2-yl-8-azabicyclo[3.2.1]oct-2-ene | 0.058 | 0.013 | 0.00034 |
| (–)-8-Methyl-3-(naphthalen-2-yl)-8-azabicylo[3.2.1]oct-2-ene | 0.034 | 0.018 | 0.00023 |
| Test Compound | DA uptake IC50(μM) | NE uptake IC50(μM) | 5-HT uptake IC50(μM) |
|---|---|---|---|
| (±)-3-(3,4-Dichlorophenyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene | 0.079 | 0.026 | 0.0047 |
| Test Compound | DA uptake IC50(μM) | NE uptake IC50(μM) | 5-HT uptake IC50(μM) |
|---|---|---|---|
| (±)-3-(4-cyanophenyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene | 18 | 4.9 | 0.047 |
| (±)-3-(4-nitrophenyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene | 1.5 | 0.5 | 0.016 |
| (±)-3-(4-trifluoromethoxyphenyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene | 22.00 | 8.00 | 0.0036 |
| Structure | Compound # (S. Singh) |
DAT (IC50 nM) displacement of [H3]WIN 35428 |
5-HTT (IC50 nM) [H3]Citalopram |
Selectivity 5-HTT/DAT |
|---|---|---|---|---|
| R/S-98a | 7.1 ± 1.7 | 5160 ± 580 | 726 | |
| R/S-98b | 9.6 ± 1.8 | 33.4 ± 0.6 | 3.5 | |
| R/S-98c | 14.3 ± 1.1 | 180 ± 65 | 12.6 |
Enantioselective nonstandard configurations (non-2β-,3β-)
β,α Stereochemistry
| Compound (RTI #) (S. Singh's #) |
X | 2 Group | config | 8 | DAT IC50 (nM) [3H]WIN 35428 |
5-HTT IC50 (nM) [3H]paroxetine |
NET IC50 (nM) [3H]nisoxetine |
selectivity 5-HTT/DAT |
selectivity NET/DAT |
| RTI-140 20a |
H | CO2Me | β,α | NMe | 101 ± 16 | 5,701 ± 721 | 2,076 ± 285 | 56.4 | 20.6 |
| RTI-352ɑ 20d |
I | CO2Me | β,α | NMe | 2.86 ± 0.16 | 64.9 ± 1.97 | 52.4 ± 4.9 | 22.8 | 18.4 |
| RTI-549 | Br | CO2Me | β,α | NMe | — | — | — | — | — |
| RTI-319b | BN | CO2Me | β,α | NMe | 1.1 | 11.4 | 70.2 | — | — |
| RTI-286c 20b |
F | CO2Me | β,α | NMe | 21 ± 0.57 | 5062 ± 485 | 1231 ± 91 | 241 | 58.6 |
| RTI-274d | F | CH2O(3′,4′-MD-phenyl) | β,α | NH | 3.96 | 5.62 | 14.4 | — | — |
| RTI-287 | Et | CO2Me | β,α | NMe | 327 | 1687 | 17,819 | — | — |
| 20c | 2.4 ± 0.2 | 998 ± 120 | 60.1 ± 2.4 | 416 | 25.0 | ||||
| 20e | 10.2 ± 0.08 | 4250 ± 422 | 275 ± 24 | 417 | 27.0 |
α,β Stereochemistry
| Compound | DA (μM) | M.E.D. (mg/kg) | Dose (mg/kg) | Activity | Activity |
| (2R,3S)-2-(4-chlorophenoxymethyl)-8-methyl-3-(3-chlorophenyl)-8-azabicyclo[3.2.1]octane | 0.39 | <1 | 50 | 0 | 0 |
| (2R,3S)-2-(carboxymethyl)-8-methyl-3-(2-naphthyl)-8-azabicyclo[3.2.1]octane | 0.1 | 1 | 25 | 0 | 0 |
| (2R,3S)-2-(carboxymethyl)-8-methyl-3-(3,4-dichlorophenyl)-8-azabicyclo[3.2.1]octane | 0.016 | 0.25 | 50 | + | +++ |
| Compound | X | 2 Group | config | 8 | DA | 5-HT | NE |
| Brasofensine | Cl2 | methyl aldoxime | α,β | NMe | — | — | — |
| Tesofensine | Cl2 | ethoxymethyl | α,β | NMe | 65 | 11 | 1.7 |
| NS-2359 (GSK-372,475) | Cl2 | Methoxymethyl | α,β | NH | — | — | — |
| Test Compound | DA uptake IC50(μM) | NE uptake IC50(μM) | 5-HT uptake IC50(μM) |
|---|---|---|---|
| (2R,3S)-2-(2,3-dichlorophenoxymethyl)-8-methyl-3-(3-chlorophenyl)-8-azabicyclo[3.2.1]octane fumaric acid salt | 0.062 | 0.035 | 0.00072 |
| (2R,3S)-2-(Naphthaleneoxymethane)-8-methyl-3-(3-chlorophenyl)-8-azabicyclo[3.2.1]octane fumaric acid salt | 0.062 | 0.15 | 0.0063 |
| (2R,3S)-2-(2,3-dichlorophenoxymethyl)-8-H-3-(3-chlorophenyl)-8-azabicyclo[3.2.1]octane fumaric acid salt | 0.10 | 0.048 | 0.0062 |
| (2R,3S)-2-(Naphthlyloxymethane)-8-H-3-(3-chlorophenyl)-8-azabicyclo[3.2.1]octane fumaric acid salt | 0.088 | 0.051 | 0.013 |
Arene equivalent alterations
η6-3β-(transition metal complexed phenyl)tropanes
Unlike metal complexed PTs created with the intention of making useful radioligands, 21a & 21b were produced seeing as their η6-coordinated moiety dramatically altered the electronic character and reactivity of the benzene ring, as well as such a change adding asymmetrical molecular volume to the otherwise planar arene ring unit of the molecule.[3]
21a was twice as potent as both cocaine and troparil in displacement of β-CFT, as well as displaying high & low affinity Ki values in the same manner as those two compounds. Whereas its inhibition of DA uptake showed it as comparably equipotent to cocaine & troparil. 21b by contrast had a one hundredfold decrease in high-affinity site binding compared to cocaine and a potency 10× less for inhibiting DA uptake.
The discrepancy in binding for the two benzene metal chelates is assumed to be due to electrostatic differences rather than their respective size difference. The solid cone angles, measured by the steric parameter (i.e. θ) is θ=131° for Cr(CO)3 whereas Cp*Ru was θ=187° or only 30% larger. The tricarbonyl moiety being considered equivalent to the cyclopenta dienyl (Cp) ligand.[3]
| Structure | Compound # (S. Singh) Systematic name |
Ki (nM)ɑ | IC50 (nM) | selectivity binding/uptake |
|---|---|---|---|---|
 |
Cocaine | 32 ± 5 388 ±221 |
405 | 12.6 |
|
11a | 33 ± 17 314 ± 222 |
373 | 11.3 |
 |
21ac | 17 ± 15b 224 ± 83 |
418 | 24.6 |
 |
21bd | 2280 ± 183 | 3890 | 1.7 |
- ɑThe binding data fit a two-site model better than a one-site model
- bThe Ki value for the one-site model was 124 ± 10 nM
- cIUPAC: [η6-(2β-carbomethoxy-3β-phenyl)tropane]tricarbonylchromium
- dIUPAC: [η5-(pentamethylcyclopentadienyl)]-[η6-(2β-carbomethoxy-3β-phenyl)tropane]ruthenium-(II) triflate
3-(2-thiophene) and 3-(2-furan)
| Code | Compound | DA (μM) | NE (μM) | 5-HT (μM) |
| 1 | (2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-methyl-3-(2-thienyl)-8-aza-bicyclo[3.2.1]octanefumaric acid salt | 0.30 | 0.0019 | 0.00052 |
| 2 | (2R,3S)-2-(1-Naphthyloxymethyl)-8-methyl-3-(2-thienyl)-8-aza-bicyclo-[3.2.1]octane fumaric acid salt | 0.36 | 0.0036 | 0.00042 |
| 3 | (2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-methyl-3-(2-furanyl)-8-aza-bicyclo-[3.2.1]octane fumaric acid salt | 0.31 | 0.00090 | 0.00036 |
| 4 | (2R,3S)-2-(1-Naphthyloxymethyl)-8-methyl-3-(2-furanyl)-8-aza-bicyclo-[3.2.1]octane fumaric acid salt | 0.92 | 0.0030 | 0.00053 |
| 5 | (2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-H-3-(2-thienyl)-8-aza-bicyclo[3.2.1]octane fumaric acid salt | 0.074 | 0.0018 | 0.00074 |
| 6 | (2R,3S)-2-(1-Naphthyloxymethyl)-8-H-3-(2-thienyl)-8-aza-bicyclo[3.2.1]octane fumaric acid salt | 0.19 | 0.0016 | 0.00054 |
Thiophenyltropanes
Diaryl
 |
 |
6/7-tropane position substituted
| Structure | Compound # (S. Singh) |
Substitution | DAT (IC50 nM) displacement of [H3]WIN 35428 |
5-HTT (IC50 nM) [H3]Citalopram |
Selectivity 5-HTT/DAT |
|---|---|---|---|---|---|
| Cocaine | H | 65 ± 12 | - | - | |
| 103a | 3β,2β, 7-OMe 3′,4′-Cl2 |
86 ± 4.7 | 884 ± 100 | 10.3 | |
| 103b | 3β,2β, 7-OH 3′,4′-Cl2 |
1.42 ± 0.03 | 28.6 ± 7.8 | 20.1 | |
| 103c | 3α,2β, 7-OH 3′,4′-Cl2 |
1.19 ± 0.16 | 1390 ± 56 | 1168 | |
| 104a | 3β,2β, 6-OH 4′-Me |
215ɑ | - | - | |
| 104b | 3β,2α, 6-OH 4′-Me |
15310ɑ | - | - | |
| 104c | 3α,2β, 6-OH 4′-Me |
930ɑ | - | - | |
| 104d | 3α,2α, 6-OH 4′-Me |
7860ɑ | - | - |
- ɑIC50 value for displacement of [H3]mazindol. IC50 for cocaine 288 nM for displacement of [H3]mazindol
| Structure | Compound # (S. Singh) |
Substituent | Ki nM displacement of [H3]mazindol binding |
Ki nM [H3]DA uptake |
Selectivity uptake/binding |
|---|---|---|---|---|---|
| Cocaine | H | 270 ± 0.03 | 400 ± 20 | 1.5 | |
| 121a | 7β-CN | 2020 ± 10 | 710 ± 40 | 0.3 | |
| 121b | 6β-CN | 3040 ± 480 | 6030 ± 880 | 2.0 | |
| 121c | 7β-SO2Ph | 4010 ± 310 | 8280 ± 1340 | 2.1 | |
| 121d | 6β-SO2Ph | 4450 ± 430 | 8270 ± 690 | 1.8 | |
| 121e | 7α-OH | 830 ± 40 | 780 ± 60 | 0.9 | |
| 121f | H | 100 ± 10 | 61 ± 10 | 0.6 | |
| 121g | 7β-CN | 24000 ± 3420 | 32100 ± 8540 | 1.3 | |
| 121h | 6β-CN | 11300 ± 1540 | 26600 ± 3330 | 2.3 | |
| 121i | 7β-SO2Ph | 7690 ± 2770 | 7050 ± 450 | 0.9 | |
| 121j | 6β-SO2Ph | 4190 ± 700 | 8590 ± 1360 | 2.0 | |
| 121k | 7α-SO2Ph | 3420 ± 1100 | - | - | |
| 121l | 7β-SO2Ph, 7α-F | 840 ± 260 | 2520 ± 290 | 3.0 | |
| 121m | 7α-F | 200 ± 10 | 680 ± 10 | 3.4 | |
| 121n | 7β-F | 500 ± 10 | 550 ± 140 | 1.1 |
| Structure | Compound # (S. Singh) |
Substituent W | Substituent X | Substituent Y | Substituent Z |
|---|---|---|---|---|---|
| (±)-122a | CN | H | H | H | |
| (±)-122b | H | H | CH | H | |
| (±)-122c | H | CH | H | H | |
| (±)-122d | H | H | H | CH | |
| (±)-122e | SO2Ph | H | H | H | |
| (±)-122f | H | H | SO2Ph | H | |
| (±)-122g | H | SO2Ph | H | H | |
| (±)-122h | SO2Ph | F | H | H | |
| (±)-122i | F | SO2Ph | H | H | |
| (±)-122j | H | H | SO2Ph | F |
8-tropane (bridgehead) position modified
Nortropanes (N-demethylated)
NS2359 (GSK-372,475)
It is well established that electrostatic potential around the para position tends to improve MAT binding. This is believed to also be the case for the meta position, although it is less studied. N-demethylation dramatically potentiates NET and SERT affinity, but the effects of this on DAT binding are insignificant.[20] Of course, this is not always the case. For an interesting exception to this trend, see the Taxil document. There is ample evidence suggesting that N-demethylation of alkaloids occurs naturally in vivo via a biological enzyme. The fact that hydrolysis of the ester leads to inactive metabolites means that this is still the main mode of deactivation for analogues that have an easily metabolised 2-ester substituent. The attached table provides good illustration of the effect of this chemical transformation on MAT binding affinities. N.B. In the case of both nocaine and pethidine, N-demethyl compounds are more toxic and have a decreased seizure threshold.[21]
| Code (S.S. #) |
X | DA | 5HT | NE |
|---|---|---|---|---|
| RTI-142 75b |
F | 4.39 | 68.6 | 18.8 |
| RTI-98 75d |
I | 0.69 | 0.36 | 11.0 |
| RTI-110 75c |
Cl | 0.62 | 4.13 | 5.45 |
| RTI-173 75f |
Et | 49.9 | 8.13 | 122 |
| N-Me compound code # → N-demethylated derivative compound code # |
para-X | [3H]Paroxetine | [3H]WIN 35,428 | [3H]Nisoxetine |
|---|---|---|---|---|
| 11g→75f | Ethyl | 28.4 → 8.13 | 55 → 49.9 | 4,029 → 122 |
| 11t→75i | vinyl | 9.5 → 2.25 | 1.24 → 1.73 | 78 → 14.9 |
| 11y→75n | Ethynyl | 4.4 → 1.59 | 1.2 → 1.24 | 83.2 → 21.8 |
| 11r→75g | 1-Propyl | 70.4 → 26 | 68.5 → 212 | 3,920 → 532 |
| 11v→75k | trans-propenyl | 11.4 → 1.3 | 5.29 → 28.6 | 1,590 → 54 |
| 11w→75l | cis-propenyl | 7.09 → 1.15 | 15 → 31.6 | 2,800 → 147 |
| 11x→75m | Allyl | 28.4 → 6.2 | 32.8 → 56.5 | 2,480 → 89.7 |
| 11z→75o | 1-Propynyl | 15.7 → 3.16 | 2.37 → 6.11 | 820 → 116 |
| 11s→75h | i-Propyl | 191 → 15.1 | 597 → 310 | 75,000 → ? |
| 11u→75j | 2-Propenyl | 3.13 → 0.6 | 14.4 → 23 | 1,330? → 144 |
| Isomer | 4′ | 3′ | NE | DA | 5HT |
|---|---|---|---|---|---|
| β,β | Me | H | 60 → 7.2 | 1.7 → 0.84 | 240 → 135 |
| β,β | F | H | 835 → 18.8 | 15.7 → 4.4 | 760 → 68.6 |
| β,β | Cl | H | 37 → 5.45 | 1.12 → 0.62 | 45 → 4.13 |
| β,α | Me | H | 270 → 9 | 10.2 → 33.6 | 4250 → 500 |
| β,α | F | H | 1200 → 9.8 | 21 → 32.6 | 5060 → 92.4 |
| β,α | Cl | H | 60 → 5.41 | 2.4 → 3.1 | 998 → 53.3 |
| β,α | F | Me | 148 → 4.23 | 13.7 → 9.38 | 1161 → 69.8 |
| β,α | Me | F | 44.7 → 0.86 | 7.38 → 9 | 1150 → 97.4 |
"Interest in NET selective drugs continues as evidenced by the development of atomoxetine, manifaxine, and reboxetine as new NET selective compounds for treating ADHD and other CNS disorders such as depression" (FIC, et al. 2005).[22]
| Short Name (S. Singh) |
Para-X | DAT [3H]WIN 35428 IC50 (nM) |
5-HTT [3H]Paroxetine IC50 (nM) |
NET [3H]Nisoxetine IC50 (nM) |
Selectivity 5-HTT/DAT |
Selectivity NET/DAT |
|---|---|---|---|---|---|---|
| Norcocaine | H | 206 ± 29 | 127 ± 13 | 139 ± 9 | 0.6 | 0.7 |
| 75a | H | 30.8 ± 2.3 | 156 ± 8 | 84.5 ± 7.5 | 5.1 | 2.7 |
| 75b | F | 4.39 ± 0.20 | 68.6 ± 2.0 | 18.8 ± 0.7 | 15.6 | 4.3 |
| 75c | Cl | 0.62 ± 0.09 | 4.13 ± 0.62 | 5.45 ± 0.21 | 6.7 | 8.8 |
| 75d | I | 0.69 ± 0.2 | 0.36 ± 0.05 | 7.54 ± 3.19 | 0.5 | 10.9 |
| 75e | para-I & 2β-CO2CH(CH3)2 |
1.06 ± 0.12 | 3.59 ± 0.27 | 132 ± 5 | 3.4 | 124 |
| 75f | C2H5 | 49.9 ± 7.3 | 8.13 ± 0.30 | 122 ± 12 | 0.2 | 2.4 |
| 75g | n-C3H7 | 212 ± 17 | 26 ± 1.3 | 532 ± 8.1 | 0.1 | 2.5 |
| 75h | CH(CH3)2 | 310 ± 21 | 15.1 ± 0.97 | - | 0.05 | - |
| 75i | CH=CH2 | 1.73 ± 0.05 | 2.25 ± 0.17 | 14.9 ± 1.18 | 1.3 | 8.6 |
| 75j | C-CH3 ║ CH2 |
23 ± 0.9 | 0.6 ± 0.06 | 144 ± 12 | 0.03 | 6.3 |
| 75k | trans-CH=CHCH3 | 28.6 ± 3.1 | 1.3 ± 0.1 | 54 ± 16 | 0.04 | 1.9 |
| 75l | cis-CH=CHCH3 | 31.6 ± 2.2 | 1.15 ± 0.1 | 147 ± 4.3 | 0.04 | 4.6 |
| 75m | CH2CH=CH2 | 56.5 ± 56 | 6.2 ± 0.3 | 89.7 ± 9.6 | 0.1 | 1.6 |
| 75n | CH≡CH | 1.24 ± 0.11 | 1.59 ± 0.2 | 21.8 ± 1.0 | 1.3 | 17.6 |
| 75o | CH≡CCH3 | 6.11 ± 0.67 | 3.16 ± 0.33 | 116 ± 5.1 | 0.5 | 19.0 |
| 75pɑ | 3,4-Cl2 | 0.66 ± 0.24 | 1.4b | - | 2.1 | - |
ɑThese values determined in Cynomolgus monkey caudate-putamen bThe radioligand used for 5-HTT was [3H]citalopram
| Short Name (S. Singh) |
DAT [125I]RTI-55 IC50 (nM) |
5-HTT [3H]Paroxetine Ki (nM) |
NET [3H]Nisoxetine Ki (nM) |
Selectivity 5-HTT/DAT |
Selectivity NET/DAT |
|---|---|---|---|---|---|
| 79a | 0.07 ± 0.01 | 0.22 ± 0.16 | 2.0 ± 0.09 | 3.1 | 28.6 |
| 79b | 4.7 ± 0.58 | 19 ± 1.4 | 5.5 ± 2.0 | 4.0 | 1.2 |
| 79c | 380 ± 110 | 5.3 ± 1.0 | 3400 ± 270 | 0.01 | 8.9 |
| 79d | 190 ± 17 | 150 ± 50 | 5100 ± 220 | 0.8 | 26.8 |
| 79e | 490 ± 120 | 85 ± 16 | 4300 ± 1100 | 0.1 | 8.8 |
| 79f | 1.5 ± 1.1 | 0.32 ± 0.06 | 10.9 ± 1.5 | 0.2 | 7.3 |
| 79g | 16 ± 4.9 | 0.11 ± 0.02 | 94 ± 18 | 0.07 | 5.9 |
| Short Name (S. Singh) |
Stereochemistry | DAT [3H]WIN 35428 IC50 (nM) |
5-HTT [3H]Paroxetine IC50 (nM) |
NET [3H]Nisoxetine IC50 (nM) |
Selectivity 5-HTT/DAT |
Selectivity NET/DAT |
|---|---|---|---|---|---|---|
| Paroxetine | - | 623 ± 25 | 0.28 ± 0.02 | 535 ± 15 | 0.0004 | 0.8 |
| R-81a | 2β,3β | 835 ± 90 | 480 ± 21 | 37400 ± 1400 | 0.6 | 44.8 |
| R-81b | 2α,3β | 142 ± 13 | 90 ± 3.4 | 2500 ± 250 | 0.6 | 17.6 |
| R-81c | 2β,3α | 3.86 ± 0.2 | 5.62 ± 0.2 | 14.4 ± 1.3 | 1.4 | 3.7 |
| S-81d | 2β,3β | 1210 ± 33 | 424 ± 15 | 17300 ± 1800 | 0.3 | 14.3 |
| S-81e | 2α,3β | 27.6 ± 2.4 | 55.8 ± 5.73 | 1690 ± 150 | 2.0 | 61.2 |
| S-81f | 2β,3α | 407 ± 33 | 19 ± 1.8 | 1990 ± 176 | 0.05 | 4.9 |
N-replaced (S,O,C)
The eight position nitrogen has been found to not be an exclusively necessary functional anchor for binding at the MAT for phenyltropanes and related compounds. Sulfurs, oxygens, and even the removal of any heteroatom, leaving only the carbon skeleton of the structure at the bridged position, still show distinct affinity for the monoamine transporter cocaine-target site and continue to form an ionic bond with a measurable degree of reasonable efficacy.
| Compound | X | 2 Group | config | 8 | DA | 5-HT | NE |
| Tropoxane | Cl,Cl | CO2Me | (racemic) β,β | O | 3.3 | 6.5 | No data |
| Structure | Compound # (S. Singh) |
Para- (meta-) |
DAT (IC50 nM) displacement of [H3]WIN 35428 |
5-HTT (IC50 nM) [H3]Citalopram |
Selectivity 5-HTT/DAT |
|---|---|---|---|---|---|
| R/S-90a | H | >1000 | >1000 | - | |
| R/S-90b | F | 546 | 2580 | 4.7 | |
| R/S-90c | Cl | 10 | 107 | 10.7 | |
| R/S-90d | Br | 22 | 30 | 1.4 | |
| R/S-90e | I | 7 | 12 | 1.7 | |
| R/S-90f | 3,4-Cl2 | 3.35 | 6.52 | 1.9 | |
| R-90g | 3,4-Cl2 | 3.27 | 4.67 | 1.4 | |
| S-90h | 3,4-Cl2 | 47 | 58 | 1.2 | |
| R/S-91a | H | 1990 | 11440 | 5.7 | |
| R/S-91b | F | >1000 | >10000 | - | |
| R/S-91c | Cl | 28.5 | 816 | 28.6 | |
| R/S-91d | Br | 9 | 276 | 30.7 | |
| R/S-91e | I | 42 | 72 | 1.7 | |
| R/S-91f | 3,4-Cl2 | 3.08 | 64.5 | 20.9 | |
| R-91g | 3,4-Cl2 | 2.34 | 31 | 13.2 | |
| S-91h | 3,4-Cl2 | 56 | 2860 | 51.1 |
N-alkyl
| Compound | X | 2 Group | config | 8 | DAT | SERT | NET |
| FP-β-CPPIT | Cl | 3′-phenylisoxazol-5′-yl | β,β | NCH2CH2CH2F | - | - | - |
| FE-β-CPPIT | Cl | (3′-phenylisoxazol-5′-yl) | β,β | NCH2CH2F | - | - | - |
| Altropane | F | CO2Me | β,β | NCH2CH=CHF | - | - | - |
| RTI-310 U.S. patent 5,736,123 | I | CO2Me | β,β | N-Prn | 1.17 | - | - |
| RTI-311 | I | CO2Me | β,β | NCH2CH=CH2 | 1.79 | - | - |
| RTI-312 U.S. patent 5,736,123 | I | CO2Me | β,β | NBun | 0.76 | - | - |
| RTI-313 U.S. patent 5,736,123 | I | CO2Me | β,β | NCH2CH2CH2F | 1.67 | - | - |
| Ioflupane | ¹²³I | CO2Me | β,β | NCH2CH2CH2F | - | - | - |
| RTI-251 | Cl | CO2Me | β,β | NCH2CO2Et | 1.93 | 10.1 | 114 |
| RTI-252 | Cl | CO2Me | β,β | NCH2CH2CO2Et | 2.56 | 35.2 | 125 |
| RTI-242 | Cl | β,β (bridged) -C(O)CH(CO2Me)CH2N | 7.67 | 227 | 510 | ||
Bi- and tri-cyclic aza compounds and their uses U.S. patent 6,150,376 WO 0007994
| Structure | Short Name (S. Singh) |
Nitrogen side-chain (N8) |
DAT [3H]GBR 12935 Ki (nM) |
5-HTT [3H]Paroxetine Ki (nM) |
NET [3H]Nisoxetine Ki (nM) |
Selectivity 5-HTT/DAT |
Selectivity NET/DAT |
|---|---|---|---|---|---|---|---|
| Cocaine | H | 350 ± 80 | >10000 | >30000 | >28.6 | - | |
| GBR 12909 | 0.06 ± 0.02 | 52.8 ± 4.4 | >20000 | 880 | - | ||
| WIN 35428 11b |
H | 14.7 ± 2.9 | 181 ± 21 | 635 ± 110 | 12.3 | 43.2 | |
| RTI-55 11e |
H | 1.40 ± 0.20 | 0.46 ± 0.06 | 2.80 ± 0.40 | 0.3 | 2 | |
| 82a | CH2CH=CH2 | 22.6 ± 2.9ɑ | - | - | - | - | |
| 82b | CH2CH2CH3 | 43.0 ± 17.7ɑ | - | - | - | - | |
| 82c | CH2C6H5 | 58.9 ± 1.65b | 1073c | - | 18.2 | - | |
| 82d | (CH2)3C6H5 | 1.4 ± 0.2b | 133 ± 7c | - | 95.0 | - | |
| 82e | (CH2)5C6H5 | 3.4 ± 0.83b | 49.9 ± 10.2c | - | 14.7 | - | |
| 83a | CH2CH2CH2F | 1.20 ± 0.29 | 48.7 ± 8.4 | 10000 | 40.6 | 8333 | |
| 83b | CH2CH2F | 4.40 ± 0.35 | 21.7 ± 8.3 | >10000 | 4.9 | - | |
| 84a | CH2CH2CH2F | 3.50 ± 0.39 | 0.110 ± 0.02 | 63.0 ± 4.0 | 0.03 | 18 | |
| 84b | CH2CH2F | 4.00 ± 0.73 | 0.140 ± 0.02 | 93.0 ± 17.0 | 0.03 | 23.2 | |
| 84c | CH2CHF2 | 15.1 ± 3.7 | 9.6 ± 1.5 | >5000 | 0.6 | - | |
| 84d | CH2CH2CH2Cl | 3.10 ± 0.57 | 0.32 ± 0.06 | 96.0 ± 29.0 | 0.1 | 31.0 | |
| 84e | CH2CH2CH2Br | 2.56 ± 0.57 | 0.35 ± 0.08 | 164 ± 47 | 0.1 | 64.1 | |
| 84f | CH2CH2CH2I | 38.9 ± 6.3 | 8.84 ± 0.53 | 5000 | 0.2 | 128 | |
| 84g | CH2...methylcyclopropane | 4.30 ± 0.87 | 1.30 ± 0.25 | 198 ± 9.6 | 0.3 | 46.0 | |
| 84h | CH2CH2CH2OH | 5.39 ± 0.21 | 2.50 ± 0.20 | 217 ± 19 | 0.5 | 40.2 | |
| 84i | CH2CH2(OCH3)2 | 6.80 ± 1.10 | 1.69 ± 0.09 | 110 ± 7.7 | 0.2 | 16.2 | |
| 84j | CH2CO2CH3 | 11.9 ± 1.4 | 0.81 ± 0.10 | 29.1 ± 1.0 | 0.07 | 2.4 | |
| 84k | CH2CON(CH3)2 | 12.2 ± 3.8 | 6.40 ± 1.70 | 522 ± 145 | 0.5 | 42.8 | |
| 84l | CH2CH2CH2OMs | 36.3 ± 2.1 | 17.3 ± 1.2 | 5000 | 0.5 | 138 | |
| 84m | COCH(CH3)2 | 2100 ± 140 | 102 ± 23 | >10000 | 0.05 | - | |
| 84n | (CH2)2Pht | 4.23 ± 0.48 | 0.84 ± 0.02 | 441 ± 66.0 | 0.2 | 104 | |
| 84o | (CH2)3Pht | 9.10 ± 1.10 | 0.59 ± 0.07 | 74.0 ± 11.6 | 0.06 | 8.1 | |
| 84p | (CH2)4Pht | 2.38 ± 0.22 | 0.21 ± 0.02 | 190 ± 18.0 | 0.09 | 79.8 | |
| 84q | (CH2)5Pht | 2.40 ± 0.17 | 0.34 ± 0.03 | 60.0 ± 3.10 | 0.1 | 25.0 | |
| 84r | (CH2)8Pht | 2.98 ± 0.30 | 0.20 ± 0.02 | 75.0 ± 3.6 | 0.07 | 25.2 | |
| 84sd | CH2CH=CH-CH3 | 15 ± 1 | 75 ± 5 | 400 ± 80 | 5.0 | 26.7 | |
| 84td | CH2C(Br)=CH2 | 30 ± 5 | 200 ± 40 | >1000 | 6.7 | - | |
| 84ud | CH2CH=CH2I(E) | 30 ± 5 | 960 ± 60 | 295 ± 33 | 32.0 | 9.8 | |
| 84vd | CH2C≡CH | 14 ± 1 | 100 ± 30 | >1000 | 7.1 | - | |
| 84wd | CH2C6H5 | 42 ± 12 | 100 ± 17 | 600 ± 100 | 2.4 | 14.3 | |
| 84xd | CH2C6H4-2-CH3 | 93 ± 19 | 225 ± 40 | >1000 | 2.4 | - | |
| 85ad | para-H | 113 ± 41 | 100 ± 20 | >1000 | 0.9 | - | |
| 85bd | para-Cl, meta-Cl | 29 ± 4 | 50 ± 6 | 500 ± 120 | 1.7 | 17.2 | |
| 85cd | para-Me | 17 ± 7 | 500 ± 30 | >1000 | 29.4 | - | |
| 85dd | para-CH(CH3)2 | 500 ± 120 | 450 ± 80 | >1000 | 0.9 | - | |
| 85ed | para-n-C3H7 | 500 ± 100 | 300 ± 12 | 750 ± 160 | 0.6 | 1.5 |
- ɑIC50 for displacement of [3H]cocaine. IC50 for cocaine = 67.8 ± 8.7 (nM)
- bIC50 values for displacement of [3H]WIN 35428
- cIC50 values for displacement of [3H]citalopram
- dThe standard Ki value for the displacement of [3H]GBR 12935, [3H]paroxetine, and [3H]nisoxetine were 27 ± 2, 3 ± 0.2, and 80 ± 28 nM, respectively, for these experiments
Tricyclic/N-constrained (inclu. N-bridged/fused/tethered)
| Compound | X | Y | R | SERT Ki (nM) | DAT Ki (nM) | NET Ki (nM) |
| 1 | Cl | Cl | CH2OCOMe | 1.6 | 1870 | 638 |
| 2 | Br | Cl | CO2Me | 2.3 | 5420 | 459 |
| 3 | I | Cl | CH2OCOPh | 0.06 | >10K | >10K |
| Compound # (S. Singh's #) |
2β=R | [3H]Mazindol binding | [3H]DA uptake | [3H]5-HT uptake | [3H]NE uptake | selectivity [3H]5-HT/[3H]DA |
|---|---|---|---|---|---|---|
| cocaine | CO2CH3 | 375 ± 68 | 423 ± 147 | 155 ± 40 | 83.3 ± 1.5 | 0.4 |
| (–)-40 (–)-128 |
54.3 ± 10.2 | 60.3 ± 0.4 | 1.76 ± 0.23 | 5.24 ± 0.07 | 0.03 | |
| (+)-40 (+)-128 |
79 ± 19 | 114 ± 28 | 1.48 ± 0.07 | 4.62 ± 0.31 | 0.01 | |
| (±)-40 (±)-128 |
61.7 ± 8.5 | 60.3 ± 0.4 | 2.32 ± 0.23 | 2.69 ± 0.12 | 0.04 | |
| 29β | 620 | 1420 | 8030 | — | — | |
| 30β | 186 | 492 | 97.7 | — | — | |
| 31β | 47.0 | 211 | 28.5 | — | — | |
| 29α | 4140 | 20100 | 3920 | — | — | |
| 30α | 3960 | 8850 | 696 | 1150 | — | |
| 45 129 |
6.86 ± 0.43 | 24.0 ± 1.3 | 1.77 ± 0.04 | 1.06 ± 0.03 | 0.07 | |
| 42a 131a |
n-Bu | 4.00 ± 0.07 | 2.23 ± 0.12 | 14.0 ± 0.6 | 2.99 ± 0.17 | 6.3 |
| 41a 130a |
n-Bu | 17.2 ± 1.13 | 10.2 ± 1.4 | 78.9 ± 0.9 | 15.0 ± 0.4 | 7.8 |
| 42b 131b |
Et | 3.61 ± 0.43 | 11.3 ± 1.1 | 25.7 ± 4.3 | 4.43 ± 0.01 | 2.3 |
| 50a 133a |
n-Bu | 149 ± 6 | 149 ± 2 | 810 ± 80 | 51.7 ± 12 | 5.4 |
| 49a 132a |
n-Bu | 13.7 ± 0.8 | 14.2 ± 0.1 | 618 ± 87 | 3.84 ± 0.35 | 43.5 |
| (–)-4 | 10500 | 16500 | 1890 | 70900 | — | |
| (+)-4 | 18500 | 27600 | 4630 | 38300 | — | |
| (–)-5 | 9740 | 9050 | 11900 | 4650 | — | |
| (+)-5 | 6770 | 10500 | 25100 | 4530 | — |
Fused tropane-derivatives as neurotransmitter reuptake inhibitors. Singh notes that all bridged derivatives tested displayed 2.5—104 fold higher DAT affinity than cocaine. The ones 2.8—190 fold more potent at DAT also had increased potency at the other two MAT sites (NET & SERT); NET having 1.6—78× increased activity. (+)-128 additionally exhibited 100× greater potency @ SERT, whereas 132a & 133a had 4—5.2× weaker 5-HTT (i.e. SERT) activity. Front-bridged (e.g. 128 & 129) had a better 5-HT/DA reuptake ratio in favor of SERT, while the back-bridged (e.g. 130—133) preferred placement with DAT interaction.[3] U.S. patent 5,998,405
| Code | Compound | DA (μM) | NE (μM) | 5-HT (μM) |
| 1 | (1 S,2S,4S,7R)-2-(3,4-Dichloro- phenyl)-8-azatricyclo[5.4.0.04,8]- undecan-11 -one O-methyl-oxime | 0.012 | 0.0020 | 0.0033 |
| 2 | (1 S,2S,4S,7R)-2-(3,4-Dichloro- phenyl)-8-azatricyclo[5.4.0.04,8]- undecan-11-one | 0.18 | 0.035 | 0.0075 |
| 3 | (1 S,3S,4S,8R)-3-(3,4-Dichloro-phenyl)-7-azatricyclo[5.3.0.04,8]- decan-5-one O-methyl-oxime | 0.0160 | 0.0009 | 0.0032 |
| 4 | (1 S,2S,4S,7R)-2-(3,4-Dichloro-phenyl)-8-azatricyclo[5.4.0.04,8]- undecan-11-ol | 0.0750 | 0.0041 | 0.0028 |
| 5 | (1 S,3S,4S,8R)-3-(3,4-Dichloro-phenyl)-7-azatricyclo[5.3.0.04,8]- decan-5-one | 0.12 | 0.0052 | 0.0026 |
| 6 | (1 S,3S,4S,8R)-3-(3,4-Dichloro- phenyl)-7-azatricyclo[5.3.0.04,8]-decan-5-ol | 0.25 | 0.0074 | 0.0018 |
| 7 | (1S,3S,4S,8R)-3- (3,4-Dichloro- phenyl)-7-azatricyclo[5.3.0.04,8]dec- 5-yl acetate | 0.21 | 0.0061 | 0.0075 |
| 8 | (1S,3S,4S,8R)-3-(3,4-Dichlorophenyl)-5-methoxy-7- azatricyclo[5.3.0.04,8]decane | 0.022 | 0.0014 | 0.0001 |
- 1-Chloroethyl chloroformate is used to remove N-methyl of trans-aryltropanes.
- 2° amine is reacted with Br(CH2)nCO2Et.
- Base used to abstract proton α- to CO2Et group and complete the tricyclic ring closure step (Dieckmann cyclization).
To make a different type of analog (see Kozikowski patent above)
- Remove N-Me
- Add ɣ-bromo-chloropropane
- Allow for cyclization with K2CO3 base and KI cat.
Cycloalkane-ring alterations of the tropane ring system
Azanonane (outer ring extended)
3-Phenyl-9-azabicyclo[3.3.1]nonane derivatives
To better elucidate the binding requirements at MAT, the methylene unit on the tropane was extended by one to create the azanonane analogs.[e] Which are the beginning of classes of modifications that start to become effected by the concerns & influences of macrocyclic stereocontrol.
Despite the loosened flexibility of the ring system, nitrogen constrained variants (such as were created to make the bridged class of phenyltropanes) which might better fit the rigid placement necessary to suit the spatial requirements needed in the binding pocket were not synthesized. Though front-bridged types were synthesized for the piperidine homologues: the trend of equal values for either isomers of that type followed the opposing trend of a smaller and lessened plasticity of the molecule to contend with a rationale for further constraining the pharmacophore within that scope. Instead such findings lend credence to the potential for the efficacy of fusing the nitrogen on an enlarged tropane, as like upon the compounds given below.
| Structure | Compound # (S. Singh) |
Ki (nM) |
|---|---|---|
|
Cocaine | 32 ± 5 390 ± 220 |
|
WIN 35065-2 | 33 ± 17 310 ± 220 |
 |
146a | 4600 ± 510 |
 |
146b | 5730 ± 570 |
 |
146c | 3450 ± 310 |
 |
146d | 3470 ± 350 |
 |
147 | 13900 ± 2010 |
Azabornane (outer ring contracted)
3-Phenyl-7-azabicyclo[2.2.1]heptane derivatives
Ring-contracted analogs of phenyltropanes did not permit sufficient penetration of the phenyl into the target binding site on MAT for an affinity in the efficacious range. The distance from the nitrogen to the phenyl centroid for 155a was 4.2 and 155c was 5.0 Å, respectively. (Whereas troparil was 5.6 & compound 20a 5.5 angstroms). However piperidine homologues (discussed below) had comparable potencies.[f]
heptane.png)
The non-carboxylic (and DAT substrate, releasing agent) variant of exo-2-phenyl-7-azabicyclo(2.2.1)heptane-1-carboxylic acid (N.B. the carboxy in the latter shares the C1 tropane position with the two carbon nitrogen containing bridge; sharing in the leftmost (R) substitution of the above depiction & unlike the placement on the tropane for either the carbmethoxy or phenyl ring of the azabornane analogues given in this section)
With the carboxy ester function removed the resultant derived compound acts as a DAT substrate drug, thus an amphetaminergic releaser of MAT & VMAT, yet similar to phenyltropanes (that usually are only re-uptake ligands)[26] cf. EXP-561 & BTQ.
Azabornanes with longer substitutions at the 3β-position (benzoyloxys alkylphenyls, carbamoyls etc.) or with the nitrogen in the position it would be on the piperidine homologues were not synthesized, despite conclusions that the nitrogen to phenyl length was the issue at variance enough to be the interfering factor for the proper binding of the compressed topology of the azabornane.
| Structure | Compound # (S. Singh) |
Ki (nM) |
|---|---|---|
|
Cocaine | 32 ± 5 390 ± 220 |
|
WIN 35065-2 | 33 ± 17 310 ± 220 |
 |
155a | 60,400 ± 4,800 |
  |
155b | 96,500 ± 42 |
 |
155c | 5,620 ± 390 |
 |
155d | 18,900 ± 1,700 |
Piperidine homologues (inner two-carbon bridge excised)
Piperidine homologues had comparable affinity & potency spreads to their respective phenyltropane analogues. Without as much of a discrepancy between the differing isomers of the piperidine class with respect to affinity and binding values as had in the phenyltropanes.
| Structure | Compound # (S. Singh) |
X = para- / 4′- Substitution |
R = 2-tropane position | DAT (IC50 nM) [H3]WIN 35428 binding displacement |
DA (IC50 nM) [H3]DA uptake |
Selectivity Uptake/Binding |
|---|---|---|---|---|---|---|
| ||||||
| Cocaine | H | CO2Me | 102 ± 9 | 239 ± 1 | 2.3 | |
 | ||||||
| (±)-166a | Cl | β-CO2CH3 | 53.7 ± 1.9 | 37.8 ± 7.9 | 0.7 | |
| (-)-166a | Cl | β-CO2CH3 | 24.8 ± 1.6 | 85.2 ± 2.6 | 3.4 | |
| (+)-166a | Cl | β-CO2CH3 | 1360 ± 125 | 5090 ± 172 | 3.7 | |
 | ||||||
| (-)-167a | Cl | β-CO2OH | 75.3 ± 6.2 | 49.0 ± 3.0 | 0.6 | |
| (+)-167a | Cl | β-CO2OH | 442 ± 32 | — | — | |
 | ||||||
| (-)-168a | Cl | β-CO2OAc | 44.7 ± 10.5 | 62.9 ± 2.7 | 1.4 | |
| (+)-168a | Cl | β-CO2OAc | 928 ± 43 | 2023 ± 82 | 2.2 | |
 | ||||||
| (-)-169a | Cl | β-n-Pr | 3.0 ± 0.5 | 8.3 ± 0.6 | 2.8 | |
 | ||||||
| (-)-170a | H | β-CO2CH3 | 769 ± 19 | — | — | |
 | ||||||
| (±)-166b | Cl | α-CO2CH3 | 197 ± 8 | — | — | |
| (+)-166b | Cl | α-CO2CH3 | 57.3 ± 8.1 | 34.6 ± 3.2 | 0.6 | |
| (-)-166b | Cl | α-CO2CH3 | 653 ± 38 | 195 ± 8 | 0.3 | |
 | ||||||
| (+)-167b | Cl | α-CO2OH | 240 ± 18 | 683 ± 47 | 2.8 | |
 | ||||||
| (+)-168b | Cl | α-CO2OAc | 461 ± 11 | — | — | |
 | ||||||
| (+)-169b | Cl | α-n-Pr | 17.2 ± 0.5 | 23.2 ± 2.2 | 1.3 |
| Structure | Compound # | [H3]DA uptake (nM) IC50 |
[H3]DA uptake (nM) Ki |
[H3]NE uptake (nM) IC50 |
[H3]NE uptake (nM) Ki |
[H3]5-HTT uptake (nM) IC50 |
[H3]5-HTT uptake (nM) Ki |
Uptake Ratio DA/5-HT (Ki) |
Uptake Ratio NE/5-HT (Ki) |
|---|---|---|---|---|---|---|---|---|---|
|
Cocaine | 459 ± 159 | 423 ± 147 | 127 ± 4.1 | 108 ± 3.5 | 168 ± 0.4 | 155 ± 0.4 | 2.7 | 0.69 |
 |
Fluoxetine | >4500 | >2500 | 193 ± 4.1 | 176 ± 3.5 | 8.1 ± 0.7 | 7.3 ± 0.7 | 624 | 24 |
 |
20 | 75 ± 9.1 | 69 ± 8.1 | 101 ± 3.3 | 88 ± 2.9 | 440 ± 30 | 391 ± 27 | 0.18 | 0.23 |
 |
6 | 23 ± 1.0 | 21 ± 0.9 | - | 34 ± 0.8 | 8.2 ± 0.3 | 7.6 ± 0.2 | 2.8 | 4.5 |
 |
7 | >1000 | 947 ± 135 | - | 241 ± 1.7 | 8.2 ± 0.3 | 7.6 ± 0.2 | 22.6 | 5.7 |
 |
8 | 94 ± 9.6 | 87 ± 8.9 | - | 27 ± 1.6 | 209 ± 17 | 192 ± 16 | 0.45 | 0.14 |
 |
9 | 293 ± 6.4 | 271 ± 5.9 | - | 38 ± 4.0 | 13 ± 0.7 | 12 ± 0.7 | 23 | 3.2 |
 |
19 | 97 ± 8.6 | 90 ± 8.0 | 34 ± 2.5 | 30 ± 2.3 | 3.9 ± 0.5 | 3.5 ± 0.5 | 26 | 8.6 |
 |
10 | 326 ± 1.2 | 304 ± 1.1 | 337 ± 37 | 281 ± 30 | 113 ± 4.3 | 101 ± 3.8 | 3.0 | 2.8 |
 |
14 | 144 ± 20 | 131 ± 18 | 204 ± 5.6 | 175 ± 4.8 | 155 ± 3.9 | 138 ± 3.5 | 0.95 | 1.3 |
 |
15 | >1800 | >1700 | >1300 | >1100 | 275 ± 39 | 255 ± 37 | >6 | >4 |
 |
16 | >1000 | 964 ± 100 | >1200 | >1000 | 334 ± 48 | 309 ± 44 | 3.1 | 3.5 |
 |
17 | 213 ± 30 | 187 ± 26 | 399 ± 12 | 364 ± 9.2 | 189 ± 37 | 175 ± 34 | 1.1 | 2.1 |
 |
18 | 184 ± 30 | 173 ± 26 | 239 ± 42 | 203 ± 36 | 67 ± 4.5 | 62 ± 4.1 | 2.8 | 3.3 |
Radiolabeled
| Code | SERT Ki (nM) | NET Ki (nM) | DAT Ki (nM) | Radiolabel | In vivo study | Refs. |
| 1 | 0.2 | 102.2 | 29.9 | 11C | Non-human primate | [29] |
| 2 | 0.2 | 31.7 | 32.6 | 11C | Non-human primate | [30] |
| 3 | 0.05 | 24 | 3.47 | 123I | Rat | [31] |
| 4 | 0.08 | 28 | 13 | 18F | Non-human primate | [32] |
| 5 | 0.11 | 450 | 22 | 11C | Rat, monkey | [33] |
-ene-2%CE%B2-carbomethoxy-3%CE%B2-(4%E2%80%B2-chlorophenyl)tropane.png)
Transition metal complexes
| Structure | Compound # (S. Singh) |
X = para- / 4′- Substitution |
Configuration | DAT (IC50 nM) displacement of [H3]WIN 35428 |
5-HTT (IC50 nM) [H3]Citalopram |
Selectivity 5-HTT/DAT |
|---|---|---|---|---|---|---|
|
WIN 35428 | F | - | 11.0 ± 1.0 | 160 ± 20 | 14.5 |
 |
73 TRODAT-1ɑ |
Cl | - | R=13.9, S=8.42b | - | - |
 |
74 TROTEC-1 |
F | - | high affinity site = 0.15 ± 0.04c low affinity site = 20.3 ± 16.1c |
- | - |
 |
89a | F | 2β | 5.99 ± 0.81 | 124 ± 17 | 20.7 |
 |
89b | F | 2α | 2960 ± 157 | 5020 ± 1880 | 1.7 |
 |
89c | 3,4-Cl2 | 2β | 37.2 ± 3.4 | 264 ± 16 | 7.1 |
 |
89d | Cl | - | 0.31 ± 0.03d | - | - |
- ɑIUPAC: [2-[[2-[[[3-(4-chlorophenyl)-7-methyl-8-azabicyclo[3,2,1]oct-2-yl]methyl]-(2-mercaptoethyl)amino]ethyl]amino]ethanethiolato-(3—)-N2, N2′, S2, S2′]oxo-[1''R''-(''exo'', ''exo'')]-[99mTc]technetium
- bR- & S- isomer values are Ki (nM) for displacement of [125I]IPT with technetium-99m replaced by rhenium
- cIC50 (nM) values for displacement of [3H]WIN 35428 with ligand tricarbonyltechnetium replaced with rhenium. (IC50 for WIN 35428 were 2.62 ± 1.06 @ high affinity binding & 139 ± 72 @ low affinity binding sites)
- dKi value for displacement of [125I]IPT radioligand.
Select annotations of above
Phenyltropanes can be grouped by "N substitution" "Stereochemistry" "2-substitution" & by the nature of the 3-phenyl group substituent X.
Often this has dramatic effects on selectivity, potency, and duration, also toxicity, since phenyltropanes are highly versatile. For more examples of interesting phenyltropanes, see some of the more recent patents, e.g. U.S. patent 6,329,520, U.S. patent 7,011,813, U.S. patent 6,531,483, and U.S. patent 7,291,737.
Potency in vitro should not be confused with the actual dosage, as pharmacokinetic factors can have a dramatic influence on what proportion of an administered dose actually gets to the target binding sites in the brain, and so a drug that is very potent at binding to the target may nevertheless have only moderate potency in vivo. For example, RTI-336 requires a higher dosage than cocaine. Accordingly, the active dosage of RTI-386 is exceedingly poor despite the relatively high ex vivo DAT binding affinity.
Sister substances
Many molecular drug structures have exceedingly similar pharmarcology to phenyltropanes, yet by certain technicalities do not fit the phenyltropane moniker. These are namely classes of dopaminergic cocaine analogues that are in the piperidine class (a category that includes methylphenidate) or benztropine class (such as Difluoropine: which is extremely close to fitting the criteria of being a phenyltropane.) Whereas other potent DRIs are far removed from being in the phenyltropane structural family, such as Benocyclidine or Vanoxerine.
See also
References
- ^ [3] ←Page #970 (46th page of article) §B, 10th line
- ^ [3] ←Page #971 (47th page of article) 1st ¶, 10th line
- ^ [3] ←Page #940 (16th page of article) underneath Table 8., above §4
- ^ [3] ←Page #941 (17th page of article) Figure 10
- ^ [3] ←Page #967 (43rd page of article) 2nd column
- ^ [3] ←Page #967 (43rd page of article) 2nd column
- ^ a b Tamagnan, Gilles (2005). "Synthesis and monoamine transporter affinity of new 2β-carbomethoxy-3β-[4-(substituted thiophenyl)]phenyltropanes: discovery of a selective SERT antagonist with picomolar potency". Bioorganic. 15 (4): 1131–1133. doi:10.1016/j.bmcl.2004.12.014. PMID 15686927.
- ^ J Pharmacol Exp Ther. 2013 Jul; 346(1): 2–10. Fig. 1. Published online 2013 Jul. doi: 10.1124/jpet.111.191056
- ^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac Chemistry, Design, and Structure-Activity Relationship of Cocaine Antagonists. Satendra Singh et al. Chem. Rev. 2000, 100. 925-1024. PubMed; Chemical Reviews (Impact Factor: 45.66). 04/2000; 100(3):925-1024 American Chemical Society; 2000, ISSN 0009-2665 ChemInform; May, 16th 2000, Volume 31, Issue 20, doi:10.1002/chin.200020238. Mirror hotlink.
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