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List of cocaine analogues

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This is an old revision of this page, as edited by 63.135.197.206 (talk) at 18:59, 9 October 2015 (→‎C-ring 2′, 3′, 4′ (5′ & 6′) position substitutions). The present address (URL) is a permanent link to this revision, which may differ significantly from the current revision.

Cocaine with its numerical substitution positions.

This is a list of cocaine analogues. A cocaine analogue retains 3β-benzoyloxy or similar functionality (the term specifically used usually distinguishes from phenyltropanes, but generally as a category includes them). Many of the semi-synthetic cocaine analogues proper which have been made & studied have consisted of among the nine following classes of compounds:[a]

  • stereoisomers of cocaine
  • 3β-phenyl ring substituted analogues
  • 2β-substituted analogues
  • N-modified analogues of cocaine
  • 3β-carbamoyl analogues
  • 3β-alkyl-3-benzyl tropanes
  • 6/7-substituted cocaines
  • 6-alkyl-3-benzyl tropanes
  • piperidine homologues of cocaine

However strict analogues of cocaine would also include such other potential combinations as phenacyltropanes & other carbon branched replacements not listed above. The term may also be loosely used to refer to drugs manufactured from cocaine or having their basis as a total synthesis of cocaine, but modified to alter their effect & QSAR. These include both intracellular sodium channel blocker anesthetics and stimulant dopamine reuptake inhibitor ligands (such as certain piperidines).

Alternate two-dimensional molecular diagram of cocaine; shown specifically as a protonated, NH+, hydrochloride, and disregarding 3D stereochemistry

Analogs sensu stricto

Cocaine Stereoisomers

There are eight stereoisomers of cocaine.[b]
Stereoisomer S. Singh's
alphanumeric
assignation 		IC50 (nM)
[3H]WIN 3542 inhibition to
rat striatal membranes
Mean error standard ≤5% in all cases 		IUPAC
nomenclature
R-cocaine - 102 methyl(1R,2R,3S,5S)-3-(benzoyloxy)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate
R-pseudococaine 172 15800
R-allococaine 173 6160
R-allopseudococaine 174 28500
S-cocaine 175 15800
S-pseudococaine 176 22500
S-allococaine 177 9820 methyl(1S,3S,4R,5R)-3-(benzoyl)oxy-8-methyl-8-azabicyclo[3.2.1]octane-4-carboxylate
S-allopseudococaine 178 67700

The creation of the following analogues of cocaine have traditionally required a step which has utilized 2-CMT as an intermediate molecular product.

Benzoyl branch cleavage substitutions (excluding the exhaustive phenyl group)

Salicylmethylecgonine[2] Methylvanillylecgonine[3][4]

N.B. Fries rearrangement product of aspirin used to make salbutamol. It is relevant to the precursor here though because the migrated acetyl group can be the subject of a haloform reaction. A more direct route to vanillic acid though is just oxidation of the vanillin to a the functionalized benzoic acid.

Arene C-ring 2′, 3′, 4′ (5′ & 6′) position substitutions


Carbon 4′-Methyl Substitutions (C-4 "para" substituted benzoyloxytropanes)[c]
Structure S. Singh's
alphanumeric
assignation
(name) 		R DAT

[3H]WIN 35428

5-HTT

[3H]Paroxetine

NET

[3H]Nisoxetine

Selectivity

5-HTT/DAT

Selectivity

NET/DAT

Satendra Singh Rev
183a I 2522 ± 4 1052 ± 23 18458 ± 1073 0.4 7.3
183b Ph 486 ± 63 - - - -
183c OAc 144 ± 2 - - - -
183d OH 158 ± 8 3104 ± 148 601 ± 11 19.6 3.8
(4′-Fluorococaine)[5] F - - - - -
(Isothiocyanatobenzoylecgonine
methyl ester)[6]
(p-Isococ)		 NCS - - - - -

File:M-Isococ.jpg File:C3benzyloxycocaine.jpg

Carbon 3′-Methyl Substitutions (C-3 "meta" substituted benzoyloxytropanes)[1]
Structure S. Singh's
alphanumeric
assignation
(name) 		R DAT

[3H]WIN 35428

5-HTT

[3H]Paroxetine

NET

[3H]Nisoxetine

Selectivity

5-HTT/DAT

Selectivity

NET/DAT

Satendra Singh Rev
184a I 325
(IC50 value for displacement of [3H]cocaine)		 - - - -
184b OH 1183 ± 115 793 ± 33 3760 ± 589 0.7 3.2
191 OBn - - - - -
(m-Isococ) NCS - - - - -

The hydroxylated 2′-OH analogue exhibited a tenfold increase in potency over cocaine.[d]

Carbon 2′-Methyl Substitutions (C-2 "ortho" substituted benzoyloxytropanes)[1]
Structure S. Singh's
alphanumeric
assignation
(name) 		R DAT

[3H]WIN 35428

5-HTT

[3H]Paroxetine

NET

[3H]Nisoxetine

Selectivity

5-HTT/DAT

Selectivity

NET/DAT

Satendra Singh Rev
185a I 350
(IC50 value for displacement of [3H]cocaine)		 - - - -
185b F 604 ± 67 1770 ± 309 1392 ± 173 2.9 2.3
185c
(2′-Acetoxycocaine)[7]		 OAc 25 ± 4 143 ± 21 48 ± 2 5.7 1.9
185d
(2′-Hydroxycocaine)[2]		 OH 215 ± 19 195 ± 10 1021 ± 75 0.9 4.7

Multi-substitutions (substitutions of substitutions; e.g. meta- & para-) or manifold ("many-fold") substituted analogues are analogues where more than one modification from the parent molecule takes place (having numerous intermediary constituents). These are created with often surprising structure–activity relationship results extrapolated therefrom. It is even a common case where two separate substitutions can each yield a weaker, lower affinity or even wholly non-efficacious compound respectively; but due to findings that oftentimes, when used together, such two mutually inferior changes being added in tandem to one analogue has the potential to make the resultant derivative display much greater efficacy, affinity, selectivity &/or strength than even the parent compound; which otherwise was compromised by either of those two alternations when made alone.

For an exposition & allusion to this mechanism observe that the opioid oxycodone, derived from codeine, is 1.5×—1.7× the analgesic potency of morphine (an opioid to which codeine is by comparison only 8%—12% as potent relatively, or 0.17th its strength in rats); yet oxycodone's intermediates in its synthesis from codeine are: ⅓ the potency of codeine (i.e. codeinone); 0.13 that of morphine (i.e. 14-hydroxycodeine) in rats and less in mice (to illustrate: the former even being less than the 0.17 of morphine that codeine is); with the final possible stand alone intermediate compound between codeine & oxycodone (i.e. 7,8-dihydrocodeine) being at most 150% to 200% that of codeine.[8]

Manifold Compositions of Terminating Phenyl Ring Substitutions (Multiple C-2,3 & 4 combined substituted benzoyloxytropanes)[1]
Structure S. Singh's
alphanumeric
assignation
(name) 		C2′=R C3′=R C4′=R DAT

[3H]WIN 35428

5-HTT

[3H]Paroxetine

NET

[3H]Nisoxetine

Selectivity

5-HTT/DAT

Selectivity

NET/DAT

File:2hydroxy4iodococaine.jpg 186 HO H I 215 ± 19 195 ± 10 1021 ± 75 0.9 4.7
(Vanillylmethylecgonine)[3] H OCH3 OH - - - - -

Terminating Phenyl Carbon Ring Fusions & Alterations[1]
Structure S. Singh's
alphanumeric
assignation
(name) 		C=R DAT

[3H]WIN 35428

5-HTT

[3H]Paroxetine

NET

[3H]Nisoxetine

Selectivity

5-HTT/DAT

Selectivity

NET/DAT

File:C2-3naphthylcocaine.jpg 187 1-naphthalene 742 ± 48
(IC50 value for displacement of [3H]cocaine)		 - - - -
File:C3-4naphthylcocaine.jpg 188 2-naphthalene 327 ± 63
(IC50 value for displacement of [3H]cocaine)		 - - - -

Benzoyl branch modifications

A selection of "front bridged" & "back bridged" cocaine analogs.


A sulfur in place of the oxygen at the benzoyl ester single bond results in a lower electronegativity than that of cocaine.

2β-substitutions (including transesterification metabolite substitution cocaethylene)

Compound 197b displayed a 1,131-fold increased selectivity in affinity for the serotonin transporter, with only slight reductions in potency for the dopamine & norepinephrine transporters.[e] Whereas 197c had a 469× increase at SERT, with greater affinity for DAT than cocaine & was approximately equipotent to NET.[f] 197b was 137×, and 196c 27× less potent at binding to the serotonin transporter, but both had a NET / DAT ratio that was better than cocaine.[g]

Direct 2β Substitutions[h]
Structure S. Singh's
alphanumeric
assignation
(name) 		R DAT

[3H]WIN 35428

5-HTT

[3H]Paroxetine

NET

[3H]Nisoxetine

Selectivity

5-HTT/DAT

Selectivity

NET/DAT

Satendra Singh Rev
(Cocaine) Me 89 ± 4.8 1045 ± 89 3298 ± 293 11.7 37.0
196a
(Cocaethylene)		 Et 195 ± 45 5801 ± 493 10000 ± 751 29.7 51.3
196b n-Pr 196 ± 46 4517 ± 430 6124 ± 262 23.3 31.2
196c i-Pr 219 ± 48 25224 ± 1498 30384 ± 1685 115 139
196d Ph 112 ± 31 33666 ± 3330 31024 ± 1909 300 277
196e Bn 257 ± 14 302 ± 23 20794 ± 950 1.2 80.9
196f β-phenethyl 181 ± 10 615 ± 52 19944 ± 1026 3.4 110
196g γ-phenylpropyl 147 ± 19 374 ± 15 4893 ± 344 2.5 33.3
196h cinnamyl 371 ± 15 368 ± 6.3 68931 ± 3476 1.0 186
196i p-NO2-β-phenethyl 601 ± 28 - - - -
196j p-Cl-β-phenethyl 271 ± 12 - - - -
196k p-NH2-β-phenethyl 72 ± 7 - - - -
196l p-NCS-β-phenethyl 196 ± 14 - - - -
196m p-azido-β-phenethyl 227 ± 19 - - - -
196n (p-NHCOCH2Br)β-phenethyl 61 ± 6 - - - -
196o (p-NHCO(CH2)2CO2Et)β-phenethyl 86 ± 4 - - - -
Satendra Singh Rev 197a NH2 753 ± 41.3 13725 ± 1256 3981 ± 229 18.2 5.3
197b -NMe2 127 ± 6.36 143713 ± 8854 7329 ± 158 1131 57.7
197c -N(OMe)Me 60 ± 6.4 28162 ± 2565 3935 ± 266 469 65.6
197d -NHMe 2424 ± 118 44798 ± 2105 4213 ± 206 18.5 1.7
197e
(Benzoylecgonine)		 -OH 195000 - - - -
Satendra Singh Rev 197f HOCH2- 561 ± 149 - - - -
197g
(Tropacocaine)		 H 5180 ± 1160 - - - -

2β-isoxazole and isoxazoline ring containing analogues[i]
Structure S. Singh's
alphanumeric
assignation
(name) 		R [3H]Mazindol [3H]DA Selectivity

Uptake/Binding

(Cocaine) (H) 580 ± 70 570 ± 180 1.0
Satendra Singh Rev
198a H 520 ± 40 260 ± 70 0.5
198b CO2Et (5′-carboethoxy-) 120 ± 10 290 ± 40 2.4
198c BOC 2230 ± 220 1820 ± 810 0.8
198d Ph 2000 ± 640 2920 ± 1620 1.5
198e CH=CHCO2Me 3600 ± 400 3590 ± 1180 1.0

nonplanar 2β-isoxazoline ring containing analogues[j]
Structure S. Singh's
alphanumeric
assignation 		R [3H]Mazindol [3H]DA Selectivity

Uptake/Binding

199a β(or R)CO2Et 710 ± 150 1060 ± 340 1.5
199b α(or S)CO2Et 5830 ± 630 8460 ± 620 1.4

2β-isoxazoline atomically N/O reversed analogues[k]
Structure S. Singh's
alphanumeric
assignation 		R [3H]Mazindol [3H]DA Selectivity

Uptake/Binding

200 880 ± 350 400 ± 140 0.4

201b & 201c show significant increased potency over cocaine; whereas 201a, 201d & 201e are considerably less so. This infers the hydrogen bond acceptor at the 2β position to not necessarily be of exclusive import in creation of higher binding analogues of cocaine.

[2H3-N-methyl]-cocaine: reagent analogue used in radio-labeling ligand binding sites.
vinylogous 2β analogues[l]
Structure S. Singh's
alphanumeric
assignation 		R [3H]Mazindol [3H]DA Selectivity

Uptake/Binding

201a H 1730 ± 550 1120 ± 390 0.6
201b Cl 222 ± 49 368 ± 190 1.6
201c CO2Et 50 ± 10 130 ± 10 2.6
201d CH=CHCO2Et 1220 ± 100 870 ± 50 0.7
201e PO(OEt)2 4850 ± 470 5500 ± 70 1.1

N-modifications

Nitrogen Substitutions (β-CFT comparison table)[m]
Compound S. Singh's
alphanumeric
assignation
(name) 		R [3H]WIN 35428 binding [3H]DA

uptake

Selectivity

uptake/binding

Satendra Singh Rev (Cocaine) CH3 102 - -
218
(Norcocaine)		 H 303 ± 59 - -
219a Bn 668 ± 67 - -
219b Ac 3370 ± 1080 - -

8-oxa cocaine analogs:[10] (cf Meltzer with PTs)
Nitrogen Substitutions (Mazindol comparison table)[n]
Compound S. Singh's
alphanumeric
assignation
(name) 		R [3H]Mazindol [3H]DA Selectivity

Uptake/Binding

Satendra Singh Rev (Cocaine) CH3 280 ± 60 320 ± 10 1.1
218
(Norcocaine)		 H - - -
219a Bn - - -
219b Ac - - -
219c CH2CH2OH 700 ± 100 1600 ± 200 2.3
219d CH2CO2CH3 480 ± 40 1600 ± 100 3.3
219e CH2CO2H 380 ± 20 2100 ± 400 5.5
220a SO2CH3 (Ms) 1290 ± 80 1970 ± 70 1.5
220b SO2CF3 (Tf) 330 ± 30 760 ± 20 2.3
220c SO2NCO 120 ± 10 160 ± 10 1.3
220d SO2Ph 20800 ± 3500 61000 2.9
220e SO2C6H4-4-NO2 (nosyl) 5720 ± 1140 18800 ± 90 3.3
220f SO2C6H4-4-OCH3 6820 ± 580 16400 ± 1400 2.4
221a NO 99500 ± 12300 231700 ± 39500 2.3
221b NO2 7500 ± 900 21200 ± 600 2.8
221c NHCOCH3 >1000000 >1000000 -
221d NH2 - - -

Tropane fused/bridged analogues

[2H5-phenyl]-cocaine: reagent analogue as above thumbnail of similar compound.
Derivations upon fusions of the tropane's nitrogen bridge[o]
Compound S. Singh's
alphanumeric
assignation 		R [3H]Mazindol [3H]DA Selectivity

Uptake/Binding

222 44900 ± 6200 115000 ± 15700 2.6

6/7 tropane position methoxycocaine analogues (including pseudococaine)

Substitutions upon the 6 & 7 positions of the tropane[p]
Compound S. Singh's
alphanumeric
assignation
(name) 		X Ki (nM)
[3H]Mazindol binding 		Ki (nM)
[3H]DA uptake 		Selectivity

Uptake/Binding

(Cocaine) 280 ± 60 320 ± 10 1.1
(Pseudococaine) 10400 ± 300 13800 ± 1500 1.3
225a 2β, 6β-OCH3 98000 ± 12000 68000 ± 5000 0.7
225b 2α, 6β-OCH3 190000 ± 11000 510000 ± 110000 2.7
225c 2β, 7β-OCH3 4200 ± 100 6100 ± 200 1.4
225d 2α, 7β-OCH3 45000 ± 5000 110000 ± 4000 2.4
225e 2α, 7α-OCH3 54000 ± 3000 200000 ± 70000 3.7

Carbon position 2′—(6′) & 2β-substitution combination analogues


4′-Iodococaine-2β-substituted analogues[q]
Compound S. Singh's
alphanumeric
assignation 		2β-R C2′-R IC50 (nM)
(displacement of [3H]WIN 35428)
211a CO2OH H 6214 ± 1269
211b CH2OCOCH3 H 2995 ± 223
211c CONHCH3 H >100000
211d CO2Et H 2031 ± 190
211e CO2-i-Pr H 1377 ± 10
211f CO2Ph H 2019 ± 253
211g CO2CH2Ph H 4602 ± 325
211h 3-phenyl-1,2,4-oxadiazole H 3459 ± 60
211i CH=CH2 H 2165 ± 253
211j CH2CH3 H 2692 ± 486
212 CH2CH3 HO 663 ± 70
4507 ± 13 for [3H]paroxetine (5-HTT & NET)
34838 ± 796 for [3H]nisoxetine (5-HTT & NET)

3β-Carbamoyl analogues



3-position carbamoyl linkage substituting benzoyloxy analogues[r]
Compound S. Singh's
alphanumeric
assignation
(name) 		X IC50 (nM)
inhibition of [3H]Cocaine binding
(Rat Striatal Tissue) 		IC50 (nM)
inhibition of [3H]DA uptake
(Rat Striatal Tissue) 		Selectivity
uptake/binding
(Cocaine) (H) 70 ± 10 210 ± 70 3.0
223a H 5600 ± 700 52600 ± 3000 9.4
223b 4-NO2 1090 ± 250 5700 ± 1200 5.2
223c 4-NH2 63300 ± 12200 >100000 -
223d 4-N3 1000 ± 240 1180 ± 360 1.2
223e 4-NCS 260 ± 60 490 ± 80 1.9
223f 3-NO2 37 ± 10 178 ± 23 4.8
223g 3-NH2 2070 ± 340 23100 ± 900 11.1
223h 3-N3 630 ± 150 3900 ± 1590 6.2
223i 3-NCS 960 ± 210 4900 ± 420 5.1

Phenyl 3-position linkage substitutions

A 3-Dimensional rendering of Troparil: A structural analogue of cocaine with omitted -COO- linkage – a parent compound of many MAT ligands; those of the phenyltropane class. (Here it is depicted in an unfavourable conformation of the O-Me; The methyl has to be at the other oxygen and trans to optimize its functional stimulation.)

See: List of phenyltropanes (Many phenyltropanes are derived from cocaine metabolites, such as methylecgonidine, as precursors)

3β-Alkylphenyltropane analogues

The compound 224e, the 3β-styrene analogue, had the highest potency in its group. While 224b & 224c showed the most selectivity, with 224b having a ten-fold greater potency for the dopamine transporter than cocaine.[s]


3-position alkylphenyl linkage substituting benzoyloxy analogues[t]
Compound S. Singh's
alphanumeric
assignation
(name) 		n IC50 (nM)
[3H]Cocaine binding 		IC50 (nM)
[3H]DA uptake 		Selectivity
uptake/binding
(Cocaine) 101 ± 26 209 ± 20 2.1
224a 1 885 ± 18 1020 ± 52 1.1
224b 2 9.9 ± 0.33 70.5 ± 1.0 7.1
224c 3 344 ± 12 2680 ± 190 7.8
224d 71.6 ± 0.7 138 ± 9 1.9
224e 2.10 ± 0.04 5.88 ± 0.09 2.8

6-Alkyl-3-benzyltropane analogues

6-Alkyl-3-benzyl-2[(methoxycarbonyl)methyl]tropane analogues[u]
Compound S. Singh's
alphanumeric
assignation
(name/WIN number) 		R Ki (nM)
[3H]WIN 35428 binding 		IC50 (nM)
[3H]DA uptake 		Selectivity

uptake/binding

(Cocaine) 32 ± 5
338 ± 221		 405 ± 91
405 ± 91		 12.6
1.2
11a
(WIN 35065-2)		 33 ± 17
314 ± 222		 373 ± 10 11.3
(−)-229a H 33 ± 5 161 ± 100 4.9
229a H 91 ± 10 94 ± 26 1.0
229b Me 211 ± 23 - -
229c Et 307 ± 28 - -
229d n-Pr 4180 ± 418 - -
229e n-Bu 8580 ± 249 - -
229f Bn 3080 ± 277 - -
(+)-230a H 60 ± 6 208 ± 63 3.5
230a H 108 ± 14 457 ± 104 4.2
230b Me 561 ± 64 - -
230c Et 1150 ± 135 - -
230d n-Pr 7240 ± 376 - -
230e n-Bu 19700 ± 350 - -
230f Bn 7590 ± 53 - -
231b Me 57 ± 5 107 ± 36 1.9
231c Et 3110 ± 187 - -
231d n-Pr 5850 ± 702 - -
231f Bn 1560 ± 63 - -
232b Me 294 ± 29 532 ± 136 1.8
232c Et 6210 ± 435 - -
232d n-Pr 57300 ± 3440 - -
232f Bn 3080 ± 277 - -
241 Bn 4830 ± 434 - -

Benzylidene derivatives of 6-alkyl-3-benzyltropanes[v]
Compound S. Singh's
alphanumeric
assignation 		R Ki (nM)
[3H]WIN 35428 binding 		IC50 (nM)
[3H]DA uptake 		Selectivity

uptake/binding

6α-isomers
237b Me - - -
237c Et - - -
237d n-Pr - - -
237e n-Bu - - -
237f Bn - - -
6β-isomers (exo)
238b Me - - -
238c Et - - -
238d n-Pr - - -
238e n-Bu - - -
238f Bn - - -
3β-benzyl derivatives
239a H - - -
239b Me - - -
239c Et - - -
239d n-Pr - - -
239e n-Bu - - -
239f Bn - - -
intermediate
alkylidene esters
240a H - - -
240b Me - - -
240c Et - - -
240d n-Pr - - -
240e n-Bu - - -
240f Bn - - -

Piperidine cocaine-homologues

binding potency of piperidine homologues for displacement of [3H]WIN 35428[w]
Compound S. Singh's
alphanumeric
assignation
(name) 		R IC50 (nM)
(Cocaine) 249 ± 37
183a 2522 ± 4
242 H 11589 ± 4
243 CO2CH3 8064 ± 4

Cocaine hapten analogues

File:CocaineAnalogGNC.jpg
"GNC", a cocaine analog designed to minimize the formation of noncocaine-like structures through its chemical coupling to the Ad proteins; all while maintaining the element of its antigenic determinant from the moiety of cocaine.[11]
Cocaine analogs which elicit noncatalytic antibodies[x]
Compound S. Singh's
alphanumeric
assignation
(name)
394
395
396
Cocaine transition state analogues (TSAs) which generate catalytic antibodies[y]
Compound S. Singh's
alphanumeric
assignation
(name) 		R
401a CH3
401b (CH2)5CO2H
401c CH2CO2H
401d COCH2CH2CO2H
401e H
401f CH2CH2Br
385g (CH2)2NHCO(CH2)2CONH2
402a O(CH2)4NHCO(CH2)2CO2…2,3-dihydro-1H-isoindole-1,3-dione
402b OH
402c O(CH2)2…1,4-xylene…NH2
402d NH(CH2)5CO2H
402e O(CH2)4NHCO(CH2)2CONH2
403a NH2
403b NHCOCH2Br
403c NHCO(CH2)3CO2H
403d (CH2)3NHCO(CH2)2CONH2
Anti-idiotypic & butyl-cholinesterase mediated immunopharmacotherapy cocaine analogs[12]
Compound Name
K1-KLH/BSA[13]
K2-KLH/BSA

Structural/Functional intermediate analogues

Tropane (non-ecgonine) analogues

pFBT: Zatosetron: Tropanserin: Bemesetronum:

Tematropium, an anticholinergic that diverges from the MAT relational criteria for being a functional analog to cocaine.[14]
  • 3-(p-Fluorobenzoyloxy)tropane (30% stimulant potency of cocaine & equipotent as an anaesthetic)
  • Zatosetron (anxiolytic & antinauseant 5HT3 receptor antagonist)
  • Tropanserin (migraine medication, potent & selective 5HT3 antagonist)
  • Bemesetronum (antiemetic, mechanisms related to oxytocin function, serotonin D-receptors, cholinoreceptors of the muscarinic or nicotinic kind and histamine H1-receptors[15])

Convolamine: File:Convolamine.jpg Phyllalbine: File:Phyllalbine.jpg
Similarly, many natural tropane alkaloids found in plants of various families have benzoyl tropane structures. Including; catuabine, convolamine of the convolvulaceae & phyllalbine of euphorbiaceae (Phyllanthus discoïdes) families. The latter is a central and peripheral sympathomimetic drug.[16]

Other tropanyl compounds (naturally found or otherwise) begin to fall outside the spectrum of functional analogues to cocaine altogether; having negligible affinity of any kind for the monoamine system. Compare for example ipratropium, mirisetron, technepine, levomepate or scopolamine & atropine. Many of the natural varieties being deliriants.

NK-1145: File:NK1145.jpg EGIS-3886:
The benzoyloxy can even be replaced with other branch formations (terminating in a benzene ring) and the bridge between will still serve to create a parasympatholytic drug compound that causes behavioral stimulation, as the above: NK-1145 "tropine-3β-phenyl ether."[17] Deramciclane (EGIS-3886) is a camphor derived serotonergic. Similar to several other kinds of aromatics in structure and being an inverse agonist at the 5-HT2C receptor as well as an antagonist at the 5-HT2A.

Piperidine Analogues

See: List of methylphenidate analogues

Many of the piperidine analogues of cocaine serve as the 'missing link' between the cocaine structure and that of the methylphenidate class of drugs. For example DMNPC preserves an orientation similar to the phenyltropanes, but is a structural isomer of methylnaphthidate.

The above depicts the 3D structure of the above-mentioned methylnaphthidate shown with the same modeling for the cocaine derivative WIN 35428, a simple phenyltropane with a short addition to its C4 position. This overlay shows the closeness of where the two hold their respective oxygen and nitrogens in their structure (also their benzene & cycloalkane ring formations) and is meant to convey a sense of their similarity for binding to MAT. Correspondingly most other monoamine reuptake inhibitors bind to the dopamine transporter substrate recognition site at Tm loci 1, 7 & 10—12; whereas cocaine & methylphenidate similarly share the 1 & 7 places, but diverge from the usual ligand site of the latter and instead cohabit the 9—11 loci.[z] Site-directed mutagenesis techniques have elucidated that the hydrophobic putative transmembrane regions at one & seven contain aspartate and serine residues, and that the carboxyl-group interacts with the former aspartic acid residue 79 which engages with cocaine & methylphenidate's protonated nitrogen at the transporter.[aa]

File:16e chemical structure.png

Benztropine (3α-Diphenylmethoxy Tropane) Analogs

  • Benzatropine
  • Difluoropine (more selective as a DARI than cocaine. Also an anticholinergic & antihistamine)
  • AHN 1-055 Same structure as for benztropine but 4′,4′-bisfluorinated.
  • GA 103 N-phenylpropyl bis-4-fluorobenztropine
  • JHW 007[19] N-(n-butyl)-3α-[bis(4′-fluorophenyl)methoxy]-tropane

"Difluoropine" is not a phenyltropane but actually belongs to the benzatropine family of DRIs.
In certain respects these are important because they share SAR overlap with GBR 12909 and related analogs.

SARs have shown that 4′,4′-difluorination is an excellent way to boost DAT activity of benztropine, and gives excellent selectivity over the SERT and the NET.[20][21]

Furthermore, replacing the N-Me with, e.g. n-phenylpropyl helps to bring muscarinic activity down to something that is the same as DRI affinity.[20]

This is remarkable considering unmodified (native) benztropine is 60 times more active as an anticholinergic than as a dopaminergic.[20]

M1 receptor considerations aside, analogues of this benztropine class still won't substitute for cocaine, and have no propensity to elevate locomotor activity.

Benztropine analog affinities binding to DAT & DA uptake
(3α-Diphenylmethoxy tropanes)[ab]
Compound S. Singh's
alphanumeric
assignation
(name) 		R R′ Ki (nM)
[3H]WIN 35428 binding 		IC50 (nM)
[3H]DA

uptake

Selectivity

uptake/binding

(Cocaine) 388 ± 47 - -
(GBR 12909) 11.6 ± 31 - -
(Benztropine) H H 118 ± 9 403 ± 115 3.4
249a 4′-F H 32.2 ± 10 48 1.5
249b 4′-F 4′-F 11.8 ± 1 71 6.0
249c 3′,4′-di-F H 27.9 ± 11 181 ± 45.7 6.5
249d 4′-Cl H 30.0 ± 12 115 3.8
249e 4′-Cl 4′-Cl 20.0 ± 14 75 3.8
249f 3′,4′-di-Cl H 21.1 ± 19 47 2.2
249g 3′,4′-di-Cl F 18.9 ± 14 24 1.3
249h 4′-Br H 37.9 ± 7 29 0.8
249i 4′-Br 4′-Br 91.6 34 0.4
249j 4′-NO2 H 197 ± 8 219 1.1
249k 4′-CN H 196 ± 9 222 1.1
249l 4′-CF3 H 635 ± 10 2155 3.4
249m 4′-OH H 297 ± 13 677 2.3
249n 4′-OMe H 78.4 ± 8 468 6.0
249o 4′-OMe 4′-OMe 2000 ± 7 2876 1.4
249p 4′-Me H 187 ± 5 512 2.7
249q 4′-Me 4′-Me 420 ± 7 2536 6.0
249r 4′-Et H 520 ± 8 984 1.9
249s 4′-t-Bu H 1918 4456 2.3
250a 3′-F H 68.5 ± 12 250 ± 64.7 3.6
250b 3′-F 3′-F 47.4 ± 1 407 ± 63.9 8.6
250c 3′-Cl H 21.6 ± 7 228 ± 77.1 10.5
250d 3′-CF3 H 187 ± 5 457 ± 72.0 2.4
251a 2′-F H 50.0 ± 12 140 ± 17.2 2.8
251b 2′-Cl H 228 ± 9 997 ± 109 4.4
251c 2′-Me H 309 ± 6 1200 ± 1.64 3.9
251d 2′-NH2 H 840 ± 8 373 ± 117 0.4
Benztropine affinities to DAT & 5-HTT in cynomologous monkey caudate-putamen
(3α-Diphenylmethoxy-2β-carbomethoxybenztropine)[ac]
Compound S. Singh's
alphanumeric
assignation
(name) 		R R′ IC50 (nM)
DAT
(Binding of [3H]WIN 35428) 		IC50 (nM)
5-HTT
(Binding of [3H]Citalopram) 		Selectivity
5-HTT/DAT
(benztropine) 312 ± 1.1 24100 ± 14800 77.2
(WIN 35428) 12.9 ± 1.1 160 ± 20 12.4
R-256 2040 ± 283 1460 ± 255 0.7
S-257a H H 33.5 ± 4.5 10100 ± 1740 301
S-257b H F 13.2 ± 1.9 4930 ± 1200 373
S-257c
(difluoropine)		 F F 10.9 ± 1.2 3530 ± 1480 324
S-257d H Cl 15.8 ± 0.95 5960 ± 467 377
S-257e Cl Cl 91.4 ± 0.85 3360 ± 1480 36.8
S-257f H Br 24.0 ± 4.6 5770 ± 493 240
S-257g Br Br 72.0 ± 3.65 2430 ± 339 33.7
S-257h H I 55.9 ± 10.3 9280 ± 1640 166
S-257i Br I 389 ± 29.4 4930 ± 82 12.7
S-257j I I 909 ± 79 8550 ± 442 9.4
S-257k H Me 49.5 ± 6.0 13200 266
S-257l Me Me 240 ± 18.4 9800 ± 2680 40.8
Benztropine affinities to DAT & 5-HTT in cynomologous monkey caudate-putamen
(N-Modified 2-carbomethoxybenztropines)[ad]
Compound S. Singh's
alphanumeric
assignation
(name) 		R n IC50 (nM)
DAT
(Binding of [3H]WIN 35428) 		IC50 (nM)
5-HTT
(Binding of [3H]Citalopram) 		Selectivity
5-HTT/DAT
258a 20.3 ± 3.5 - -
258b H 1 223 ± 53 4970 ± 700 22.3
258c H 3 22.0 ± 11.9 19.7 ± 3 0.9
258d Br 3 80.2 ± 8.8 234 ± 0.5 2.9
258e I 3 119 ± 11 2200 ± 1250 18.5
258f H 5 99.0 ± 28 550 ± 63 5.5
259 616 ± 88 55200 ± 20000 89.3
Benztropine affinities to DAT & 5-HTT
(N-substituted 3α[bis(4′-fluorophenyl)methoxy]tropanes)[ae]
Compound S. Singh's
alphanumeric
assignation
(name) 		R Ki (nM)
DAT
(Binding of [3H]WIN 35428) 		IC50 (nM)
5-HTT
(Uptake of [3H]DA) 		Selectivity
uptake/binding
260 H 11.2 ± 11 9.7 0.9
261a 3-phenylpropyl 41.9 ± 11 230 5.5
261b indole-3-ethyl 44.6 ± 11 1200 26.9
261c 4-phenylbutyl 8.51 ± 14 39 4.6
261d 4-(4′-nitrophenyl)butyl 20.2 ± 11 650 32.2
261e 3-(4′-fluorophenyl)propyl 60.7 ± 12 - -
262a n-butyl 24.6 ± 8 370 15.0
262b cyclopropylmethyl 32.4 ± 9 180 5.5
262c allyl 29.9 ± 10 14 0.5
262d benzyl 82.2 ± 15 290 3.5
262e 4-fluorobenzyl 95.6 ± 10 200 2.1
262f cinnanyl 86.4 ± 12 180 2.1
262g [bis(4-fluorophenyl)methoxy]ethyl 634 ± 23 - -
262h [(4-nitrophenyl)phenylmethoxy]ethyl 57.0 ± 17 - -
263 acetyl 2340 4600 2.0
264 formyl 2020 ± 13 5400 2.7
265a Ts 0%
(inhibition at 10 µM)		 - -
265b Ms 18%
(inhibition at 10 µM)		 - -
266 108 ± 12 130 1.2
8-Oxanortropane benztropine analog affinities to DAT & 5-HTT
(8-Oxa-2-carbomethoxy norbenztropines)[af]
Compound S. Singh's
alphanumeric
assignation
(name) 		IC50 (nM)
DAT
(Binding of [3H]WIN 35428) 		IC50 (nM)
5-HTT
(Binding of [3H]Citalopram)
R/S-268 2β,3β >10000 >1660
R/S-269 2α,3β 20300 >1660
R/S-270 2α,3α 22300 >1660
R/S-271 2β,3α 520 >1660

Bicyclic Amine Analogues

Quinuclidine Analogues

Miscellaneous loosely analogous stimulants

Strobamine, a DARI functional cocaine analog.[22]

Benzoates (Structures with both stimulant & local anesthetic effects)

See some of Robert Clarke's contributions

Chromen-2-one

File:Chromen-2-one.jpg

US 2011136854 
Compound DA-uptake IC50(μM) NA-uptake IC50(μM) 5-HT-uptake IC50(μM)
7-(((1R,3r,5S)-9-Azabicyclo[3.3.1]nonan-3-yl)oxy)-2H-chromen-2-one 0.0013 0.24 0.076
7-(((1R,3r,5S)-9-Methylazabicyclo[3.3.1]nonan-3-yl)oxy)-2H-chromen-2-one 0.0029 0.15 0.27

Organochlorides

Org 6582
A potent and long-lasting monoamine re-uptake inhibitor used in drug research.

2,3-Benzodiazepines

Phenethylamines

Many phenethylamines are dopamine releasers, however, certain drugs of the family inhibit dopamine reuptake & transport which may be loosely classed as cocaine analogs. Dependent upon their specific configurations.

Adamantanes

Naphthyridines

Being a carboxylic acid, amfonelic acid could potentially be used as a carboxylate for the protonation to the free base of another compound; even conceivably creating a 'cocaine amfonelate' or 'cocaine AFA' as opposed to cocaine HCl, cocaine citrate or cocaine HBr et cetera wherein such a case it's conjugate used to form it as a salt would additionally be dopaminergic.

Quinazolinamines (Allosteric functional DAT reuptake inhibitors)

cf. the benztropine phenyltropanes:

SoRI-20041 is a functional, but not structural, cocaine analog which violates traditional structure analog categorization in its case that it has an entirely other binding site. It is however an analog to cocaine in the sense that it functions as a partial DARI on DAT, although doing so when said DAT is compromised by amphetamine-type mediated release of DA. Something unaugmented cocaine cannot do. It nevertheless performs the role of an analogous adjunct to cocaine's function for phosphorylated DAT. It is however worth noting that as for its structure, it displays a certain degree of shared conformation with the benztropine phenyltropanes.

Piperazines (Aryl-1,4-dialkyl piperazines)

GBR-13098: 281 (decanoate 5):

GBR compounds were derived from the benztropines by replacing their tropane nucleus with a piperazine ring.[ag]

GBR 12783 analogues inhibition of DAT binding & DA uptake[ah]
Compound S. Singh's
alphanumeric
assignation
(name) 		R Ki (nM)
[3H]WIN 35425 		IC50 (nM)
[3H]DA 		Selectivity
uptake/binding
(Cocaine) 224 ± 3.4 208 ± 7.4 0.93
(WIN 35428) 24 ± 3.1 14 ± 1.8 0.58
(DA) 10000 ± 2400 44 ± 5.3 0.004
279
(GBR 12909/Vanoxerine)		 27 ± 4.1 0.21 ± 0.06 0.007
282
(GBR 12783)		 H 12 ± 1.2
(IC50 for inhibiting [3H]methylphenidate)		 - -
284a 3-NH2 12 ± 1.0 7 ± 3.5 0.58
284b 3-NCS 160 ± 17 106 ± 37 0.67
284c 4-NH2 11 ± 0.7 1.6 ± 0.2 0.14
284d 4-NO2 26 ± 9.3 2.7 ± 0.1 0.10
284e 4-NCS 159 ± 12 26 ± 1.8 0.16
284f 4-maleimide 2327 ± 1000 476 ± 61 0.20
GBR analogue compounds with piperazine ring-alterations. Binding affinities and inhibition of uptake for DA & 5-HT.[ai]
Compound S. Singh's
alphanumeric
assignation
(name) 		R X-Y (289-290)
R1 (298) 		IC50 (nM)
[3H]GBR 12935 binding 		IC50 (nM)
[3H]DA uptake 		IC50 (nM)
[3H]5-HT uptake 		Selectivity
[3H]DA uptake/DAT binding 		Selectivity
[3H]5-HT/[3H]DA uptake
(Cocaine) 660 ± 30
(Ki value)		 478 ± 25 304 ± 10 0.72 0.64
(GBR 12935) 4.1 ± 0.6 3.7 ± 0.4 289 ± 29 0.90 78.1
279
(GBR 12909)		 5.5 ± 0.4 4.3 ± 0.3 73 ± 1.5 0.78 17.0
289a H C-C 21 ± 1.0 9.6 ± 1.5 1720 ± 70 0.46 179
289b F C-C 40 ± 1 15 ± 2 459 ± 26 0.37 30.6
(-)289b (2S,5R) F C-C 3.6 ± 0.14 8.1 ± 0.3 - 2.25 -
(+)289b (2R,5S) F C-C 125 ± 7.0 87 ± 4.1 - 0.70 -
289c H C=C 103 ± 13 20 ± 4 2680 ± 122 0.19 134
289d F C=C 23 ± 3 28 ± 5 1180 ± 404 1.22 42.1
290a
(LR1111)		 H C-C 7.9 ± 1.7 7.2 ± 0.5 34100 ± 359 0.91 4736
290b F C-C 4.4 ± 0.4 3.4 ± 0.4 112 ± 24 0.77 32.9
290c H C=C 8.6 ± 1.1 0.6 ± 0.1 503 ± 103 0.07 838
290d F C=C 2.6 ± 0.4 3.4 ± 0.4 234 ± 10 1.31 68.8
291 286 ± 8 87 ± 5 3150 ± 491 0.30 36.2
292 864 ± 91 93 ± 6 1590 ± 60 0.11 17.1
293 27 ± 4 18 ± 1 2450 ± 57 0.67 136
294 169 ± 5 83 ± 7 1890 ± 268 0.49 22.8
295 80 ± 6 35 ± 2 376 ± 19 0.44 10.7
296 74 ± 5 57 ± 10 2860 ± 45 0.77 50.2
297 20 ± 0.7 9.3 ± 1.8 1480 ± 69 0.46 159
(-)298a H H 5.1 ± 0.4 0.7 ± 0.05 986 ± 34 0.14 1409
(+)298a H H 747 ± 163 127 ± 10 3210 ± 450 0.17 25.3
(-)298b F H 104 ± 8 29 ± 2 20100 ± 2400 0.28 693
(-)298c H OH 222 ± 13 31 ± 0.1 857 ± 17 0.14 27.6
Heteroaromatic and fused ring GBR analogue affinities reuptake inhibition for DA & 5-HT and [125I]RTI-55 labeled DAT & 5-HTT binding affinities.[aj]
Compound S. Singh's
alphanumeric
assignation
(name) 		R R1 IC50 (nM)
[125I]RTI-55 binding
DAT 		IC50 (nM)
[125I]RTI-55 binding
5-HTT 		IC50 (nM)
reuptake
[3H]DA 		IC50 (nM)
reuptake
[3H]5-HT 		Selectivity
binding
5-HTT/DAT 		Selectivity
uptake
[3H]5-HT/[3H]DA
(GBR 12935) C6H5 3.7 ± 0.3 623 ± 13 3.7 ± 0.4 298 ± 29 168 80.5
304a 2-thienyl 5.2 ± 0.3 842 ± 30 9.7 ± 0.2 1990 ± 58 162 205
304b 2-furyl 6.5 ± 0.2 1520 ± 47 8.5 ± 0.5 2550 ± 87 34 300
304c 2-pyridyl 78 ± 4 2420 ± 65 70 ± 6 3700 ± 148 31.0 52.8
279 (GBR 12909) C6H5 3.7 ± 0.4 126 ± 5 7.3 ± 0.2 73 ± 2 34.0 10.0
305a 2-thienyl 3.3 ± 0.1 105 ± 2 6.1 ± 0.7 335 ± 17 31.8 54.9
305b 2-furyl 5.9 ± 0.3 204 ± 7 7.9 ± 0.5 412 ± 9 34.6 52.1
305c 2-pyridyl 16 ± 0.2 2800 ± 139 20 ± 0.8 6520 ± 293 175 326
282 (GBR 12783) C6H5 - - - - - -
306a 2-thienyl 6.4 ± 0.3 1170 ± 31 10 ± 0.7 2020 ± 141 183 202
306b 2-furyl 5.0 ± 0.3 1840 ± 59 9.6 ± 0.3 2700 ± 136 368 281
306c 2-pyridyl 44 ± 3 2670 ± 66 64 ± 2 3620 ± 179 60.7 56.6
283 (GBR 13069) C6H5 0.9 ± 0.1 135 ± 7 11 ± 0.6 576 ± 32 150 52.4
307a 2-thienyl 2.2 ± 0.1 88 ± 2 13 ± 1.4 374 ± 17 40.0 28.8
307b 2-furyl 1.8 ± 0.3 109 ± 4 7.2 ± 0.4 442 ± 23 60.5 61.4
307c 2-pyridyl 13.6 ± 0.2 334 ± 12 14.5 ± 1.9 666 ± 21 24.5 45.9
308a H (benzothiophen-2-yl)methyl 18.1 ± 1 2420 ± 109 19 ± 1 3520 ± 289 134 185
308b F (benzothiophen-2-yl)methyl 4.1 ± 1.1 495 ± 18 34 ± 2 1230 ± 40 121 36.2
309a H (benzofuran-2-yl)methyl 17 ± 0.5 1890 ± 48 22 ± 0.7 3040 ± 213 111 138
309b F (benzofuran-2-yl)methyl 6.4 ± 0.2 286 ± 10 18.6 ± 0.6 767 ± 27 44.7 41.2
310a H (indol-2-yl)methyl 1.1 ± 0.1 668 ± 39 8.8 ± 0.7 2120 ± 166 607 241
310b F (indol-2-yl)methyl 0.7 ± 0.1 119 ± 5 13 ± 0.2 506 ± 23 170 38.9
311a H (benzimidazol-2-yl)methyl 46 ± 1 1884 ± 72 37 ± 2 4076 ± 221 41.0 110
311b F (benzimidazol-2-yl)methyl 15 ± 0.2 256 ± 7 20 ± 0.8 797 ± 43 17.1 39.8
312a H (quinolin-2-yl)methyl 199 ± 5 1990 ± 5 192 ± 8 4120 ± 212 10.0 21.5
312b F (quinolin-2-yl)methyl 56 ± 1 51 ± 16 106 ± 12 339 ± 31 0.9 3.2
313a H (quinolin-3-yl)methyl 72 ± 2 1160 ± 27 111 ± 3 3040 ± 252 16.1 27.4
313b F (quinolin-3-yl)methyl 16 ± 3 485 ± 16 74 ± 3 851 ± 36 30.3 11.5
314a H (quinolin-6-yl)methyl 190 ± 6 845 ± 15 140 ± 4 1640 ± 58 4.4 11.7
314b F (quinolin-6-yl)methyl 62 ± 2 551 ± 21 73 ± 3 1040 ± 46 8.9 14.2
315a H 3-(benzimidazol-2-yl)propyl 23 ± 0.5 309 ± 9 17 ± 0.7 627 ± 12 13.4 36.9
315b F 3-(benzimidazol-2-yl)propyl 2.5 ± 0.1 28 ± 2 8.1 ± 0.3 74 ± 4 11.2 9.1
316a H (naphthalen-2-yl)methyl 43 ± 2 903 ± 47 32 ± 0.6 926 ± 33 21.0 28.9
316b F (naphthalen-2-yl)methyl 8.0 ± 0.3 312 ± 15 30 ± 1 588 ± 39 39.0 19.6
317a H (naphthalen-1-yl)methyl 114 ± 5 336 ± 22 406 ± 11 83 ± 5 2.9 0.2
317b F (naphthalen-1-yl)methyl 31 ± 1 243 ± 6 312 ± 19 257 ± 12 7.8 0.8
318a H 2-(naphthalen-1-yl)ethyl 92 ± 13 462 ± 17 42 ± 0.9 578 ± 17 5.0 13.8
318b F 2-(naphthalen-1-yl)ethyl 7.8 ± 0.2 46 ± 1 25 ± 0.8 119 ± 4 5.9 4.8
Piperidine analogues of piperazine GBR compounds & their affinity to bind at DAT & 5-HTT[ak]
Compound S. Singh's
alphanumeric
assignation
(name) 		R R′ R″ IC50 (nM)
DAT
[3H]WIN 35428 		IC50 (nM)
5-HTT
[3H]citalopram 		Selectivity
5-HTT/DAT
279 (GBR 12909) 14.0 ± 0.6 82 ± 4 5.8
320 (O-549) 595 ± 148 38 ± 127 0.6
321 (O-526) F 24.9 ± 3.23 248 ± 72 9.9
322a H 12.0 ± 0.4 232 ± 28 19.3
322b Cl 65.0 ± 12 224 ± 10 3.4
322c Br 159 ± 56 835 ± 142 5.2
322d OCH3 255 ± 32 340 ± 24 1.3
323a H 10.6 ± 0.85 102 ± 5 9.6
323b F 19.9 ± 9.5 31.9 ± 7.1 1.6
323c Cl 115 ± 22 414 ± 32 3.6
323d Br 382 ± 167 638 ± 71 1.7
323e CH3 311 ± 71 888 ± 58 2.8
324a H 15.2 ± 2.8 743 ± 6 48.9
324b F 9.7 ± 0.4 198 ± 7 20.4
325a H 14.5 ± 1.9 58 ± 7 3.7
325b F 13.0 ± 2.5 112 ± 4 8.6
326a H 108 ± 14 456 ± 90 4.2
326b F 13.5 ± 2.6 237 ± 53 17.5
327a H 702 ± 34 544 ± 91 0.8
327b F 126 ± 13 761 ± 101 6.0
328a H H F 17.2 ± 4.7 1920 ± 233 111.6
328b H H Cl 24.7 ± 5.5 1610 ± 119 65.2
328c H H Br 31.1 ± 2.9 1490 ± 319 47.9
328d H Cl Cl 85.7 ± 4.7 2880 ± 281 33.6
328e H H OCH3 27.8 ± 6.8 1240 ± 342 44.6
328f Cl H F 52.4 ± 7.8 1810 ± 107 34.5
328g F H F 14.0 ± 3.3 1260 ± 72 90.0
328h H H CH3 23.0 ± 3.7 1390 ± 240 60.4
328i H Cl F 28.2 ± 3.1 2530 ± 50 89.7
328j H H NO2 16.4 ± 3.0 1770 ± 305 107.9
328k H H NH2 101 ± 13 1570 ± 201 15.5
329a Ph 3-pyridyl 48.6 ± 8.4 680 ± 12.0 14.0
329b Ph 2-benzo[b]thiophenyl 172 ± 16.4 1540 ± 251 8.9
329c Ph 2-thienyl 59.3 ± 5.8 1250 ± 87 21.1
329d 2-thienyl Ph 27.2 ± 0.1 741 ± 108 27.2
329e 2-thienyl 4-F-Ph 13.8 ± 3.4 1390 ± 243 101
329f 2-thienyl 3-pyridyl 58.3 ± 5.7 927 ± 34 15.9
330a F 4-F-Ph 15.1 ± 2.0 75.8 ± 22.1 5.0
330b F Ph 41.4 ± 8.0 271 ± 18.4 6.5
330c H Ph 10.1 ± 1.6 231 ± 4.5 22.9
330d H 4-F-Ph 10.8 ± 3.2 205 ± 13.3 19.0
330e H 2-thienyl 9.8 ± 2.4 290 ± 63 29.6
331a Ph H 4-F-Ph 6.6 ± 1.4 223 ± 32.3 33.8
331b Ph H 3-pyridyl 29.9 ± 0.3 194 ± 20.1 6.5
331c 2-thienyl H Ph 6.0 ± 0.5 180 ± 21.6 30.0
331d 2-thienyl F Ph 11.7 ± 1.0 85.7 ± 2.6 7.3
332a H F 9.4 ± 2.6 585 ± 101 62.2
332b F H - - -

Dihydroimidazoles

Possible substitutions of the Mazindol molecular structure.

See: List of Mazindol analogues, a non-habituating tetracyclic dopamine reuptake inhibitor (of somewhat spurious classification in the former) and loosely functional analog used in cocaine research.

The above steps in its synthesis show the similitude of its precursors to the MAT reuptake inhibitor pipradrol & related compounds.

Local anesthetics (not usually CNS stimulants)

File:Beta-Eucaine.jpg
β-Eucaine (Betacain)

In animal studies, certain of the local anesthetics have displayed residual dopamine reuptake inhibitor properties,[23] although not normally ones that are easily available. These are expected to be more cardiotoxic than phenyltropanes. For example, dimethocaine has behavioral stimulant effects (and therefore not here listed below) if a dose of it is taken that is 10 times the amount of cocaine. Dimethocaine is equipotent to cocaine in terms of its anesthetic equivalency.[23]

List of local anesthetics
Name Other common names
Amylocaine Stovaine
Articaine Astracaine, Septanest, Septocaine, Ultracaine, Zorcaine
Benzocaine
Bupivacaine Marcaine, Sensorcaine, Vivacaine
Butacaine
Carticaine
Chloroprocaine Nesacaine
Cinchocaine/Dibucaine Cincain, Cinchocaine, Nupercainal, Nupercaine, Sovcaine
Cyclomethycaine Surfacaine, Topocaine
Etidocaine
Eucaine α-eucaine, ß-eucaine
Hexylcaine Cyclaine, Osmocaine
Levobupivacaine Chirocaine
Lidocaine/Lignocaine Xylocaine, Betacaine
Mepivacaine Carbocaine, Polocaine
Meprylcaine/Oracaine Epirocain
Metabutoxycaine Primacaine
Phenacaine/Holocaine
Piperocaine Metycaine
Pramocaine/Pramoxine
Prilocaine Citanest
Propoxycaine/Ravocaine
Procaine/Novocaine Borocaine (Procaine Borate), Ethocaine
Proparacaine/Alcaine
Quinisocaine Dimethisoquin
Risocaine
Ropivacaine Naropin
Tetracaine/Amethocaine Pontocaine, Dicaine
Trimecaine Mesdicain, Mesocain, Mesokain

Analogues for other purposes

Tropanes (Non-ecgonine)

Benzamides

Mefexamide is not a benzamide, but it has structure that is related and is described as a central stimulant, and therefore more correctly a "functional analog". cf. the benzoate stimulants

Toxins

Cocaine to Anatoxin-a:[24]
  • Anatoxin-a, also known as "Very Fast Death Factor" (VFDF), is an acutely toxic cyanotoxin with a method of action as an agonist of acetylcholine via those nicotinic class of receptors. Cocaine can be used as a precursor in its synthesis.

VFDF
Note its eight, instead of seven, sides
(not counting the nitrogen-bridge inside ring)
cf. methylecgonidine, a pyrolysis product of cocaine freebase.
cf. also: ferruginine, a compound even more analogous to the former.[25]

See also

Cocaine-N-oxide: File:Cocaine N-oxide.jpg Hydroxytropacocaine: File:Hydroxytropacocaine.jpg m-Hydroxybenzoylecgonine: File:M-Hydroxybenzoylecgonine.jpg

Methylecgonine cinnamate, an alkaloid inactive in its own right, but postulated to be active under pyrolysis. (cf alkylphenyltropane analogue "224e")
Cocaine HCl hydrolyzes in moist air to become the above compound; methyl benzoate

Common analogues to prototypical DRAs:

References

  1. ^ 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 ad ae af ag ah ai aj ak al am an 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.
  2. ^ a b Singh S, Basmadjian GP, Avor K, Pouw B, Seale TW. A convenient synthesis of 2′- or 4′-hydroxycocaine. Synthetic Communications. 1997;27(22):4003-4012.
    et. el-Moselhy TF, Avor KS, Basmadjian GP. 2′-substituted analogs of cocaine: synthesis and dopamine transporter binding potencies. Archiv der Pharmazie (Weinheim). 2001 Sep;334(8-9):275-8. PMID 11688137
    et. Seale TW, Avor K, Singh S, Hall N, Chan HM, Basmadjian GP. 2′-Substitution of cocaine selectively enhances dopamine and norepinephrine transporter binding. Neuroreport. 10 November 1997;8(16):3571-5. PMID 9427328
  3. ^ a b Smith, R. Martin; Poquette, Michael A.; Smith, Paula J.,
  4. ^ "Hydroxymethoxybenzoylmethylecgonines: New metabolites of cocaine from human urine." Journal of Analytical Toxicology 1984, 8(1), pp.29-34
  5. ^ Gatley SJ, Yu DW, Fowler JS, MacGregor RR, Schlyer DJ, Dewey SL, Wolf AP, Martin T, Shea CE, Volkow ND (March 1994). "Studies with differentially labeled [11C]cocaine, [11C]norcocaine, [11C]benzoylecgonine, and [11C]- and 4′-[18F]fluorococaine to probe the extent to which [11C]cocaine metabolites contribute to PET images of the baboon brain". Journal of Neurochemistry. 62 (3): 1154–62. doi:10.1046/j.1471-4159.1994.62031154.x. PMID 8113802.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  6. ^ "Cocaine Receptor: Biochemical Characterization and Structure-Activity Relationships of Cocaine Analogues at Dopamine Transporter". Journal of Medicinal Chemistry. 35 (6): 969–981. 1992. doi:10.1021/jm00084a001. PMID 1552510. {{cite journal}}: Cite uses deprecated parameter |authors= (help)
  7. ^ Seale, TW; Avor, K; Singh, S; Hall, N; Chan, HM; Basmadjian, GP (1997). "2′-Substitution of cocaine selectively enhances dopamine and norepinephrine transporter binding". Neuroreport. 8 (16): 3571–5. doi:10.1097/00001756-199711100-00030. PMID 9427328.
  8. ^ The analgesic properties of some 14-substituted derivatives of codeine and codeinone J. Pharm. Pharmacol., Royal Pharmaceutical Society of Great Britain, 1964, 16, 174—182. doi: 10.1111/j.2042-7158.1964.tb07440.x
  9. ^ Benzoylthio-. cocaine, analogue substitution. Synthesis, Properties, and Reactivity of Cocaine Benzoylthio Ester Possessing the Cocaine Absolute Configuration. Shigeki Isomura, Timothy Z. Hoffman, Peter Wirsching, and Kim D. Janda. J. Am. Chem. Soc., 2002, 124 (14), pp 3661–3668 DOI: 10.1021/ja012376y Publication Date (Web): March 14, 2002.
  10. ^ Kozikowski, A. P.; Simoni, D.; Roberti, M.; Rondanin, R.; Wang, S.; Du, P.; Johnson, K. M. (1999). "Synthesis of 8-oxa analogues of norcocaine endowed with interesting cocaine-like activity". Bioorganic & Medicinal Chemistry Letters. 9 (13): 1831. doi:10.1016/S0960-894X(99)00273-5.
  11. ^ "Cocaine Analog Coupled to Disrupted Adenovirus: A Vaccine Strategy to Evoke High-titer Immunity Against Addictive Drugs" PMCID: PMC3048190 doi: 10.1038/mt.2010.280
  12. ^ Inhibition of Cocaine Binding to the Human Dopamine Transporter by a Single Chain Anti-Idiotypic Antibody: Its Cloning, Expression and Functional Properties Biochim Biophys Acta. 2003 Jul 30; 1638(3): 257–266. PMCID: PMC3295240 NIHMSID: NIHMS358284
  13. ^ Exploring the feasibility of an anti-idiotypic cocaine vaccine: analysis of the specificity of anticocaine antibodies (Ab1) capable of inducing Ab2βanti-idiotypic antibodies Immunology. 2000 May; 100(1): 48–56. PMCID: PMC2326984 doi: 10.1046/j.1365-2567.2000.00004.x
  14. ^ Soft drugs— Synthesis and anticholinergic activity of soft phenylsuccinic analogs of methatropine Bioorganic & Medicinal Chemistry: Volume 1, Issue 3, September 1993, Pages 183–187
  15. ^ Bemesetron @ U.S. National Library of Medicine's TOXNET: Toxicology Data Network
  16. ^ An alkaloid of Phyllanthus discoides (Euphorbiaceae) phyllalbine, a central and peripheral sympathomimetic (Impact Factor: 0.4). 01/1965; 20(4):1033-41
  17. ^ ARZNAD Arzneimittel-Forschung. Drug Research. (Editio Cantor Verlag, Postfach 1255, W-7960 Aulendorf, Fed. Rep. Ger.) V.1-1951-Volume(issue)/page/year: 18,517,1968
  18. ^ Dopamine reuptake transporter (DAT) ``inverse agonism´´ - A novel hypothesis to explain the enigmatic pharmacology of cocaine 2014-12-24 17:08:48 2014-12-25 00:28:27
  19. ^ Tanda G, Newman A, Ebbs AL, Tronci V, Green J, Tallarida RJ, Katz JL.Combinations of Cocaine with other Dopamine Uptake Inhibitors: Assessment of Additivity. J Pharmacol Exp Ther. 2009 May 29. PMID 19483071
  20. ^ a b c Rothman RB, Baumann MH, Prisinzano TE, Newman AH. Dopamine transport inhibitors based on GBR12909 and benztropine as potential medications to treat cocaine addiction. Biochem Pharmacol. 2008 Jan 1;75(1):2-16. doi:10.1016/j.bcp.2007.08.007 PMID 17897630
  21. ^ Runyon SP, Carroll FI. Dopamine transporter ligands: recent developments and therapeutic potential. Curr Top Med Chem. 2006;6(17):1825-43. doi:10.2174/156802606778249775 PMID 17017960
  22. ^ Enantioselective synthesis of strobamine and its analogues Xing Zhang et al. Center for Organic and Medicinal Chemistry, Research Triangle Institute. Issue in Honor of Prof. James M.Cook ARKIVOC 2010 (iv)96-103
  23. ^ a b Wilcox, K.M., Kimmel, H.L., Lindsey, K.P., Votaw, J.R., Goodman, M.M., Howell, L.L. In vivo comparison of the reinforcing and dopamine transporter effects of local anesthetics in rhesus monkeys. Synapse, 58: 220-228, 2005. PDF
  24. ^ Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1016/S0957-4166(00)00059-8, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1016/S0957-4166(00)00059-8 instead.
  25. ^ Approaches to the enantioselective synthesis of ferrugine and its analogues Institute of Chemistry, University of Bialystok, ul. Hurtowa 1, 15-339 Bialystok, Poland

Notes

  1. ^ [1] ←Page #969 (45th page of article) §III. ¶1. Final line. Last sentence.
  2. ^ [1] ←Page #970 (46th page of article) Table 27. Figure 29.
  3. ^ [1] ←Page #971 (47th page of article) Figure 30. & Page #973 (49th page of article) Table 28.
  4. ^ [1] ←Page #972 (48th page of article) ¶2, Line 10.
  5. ^ [1] ←Page #974 (50th page of article) Final ¶ (5th), Second line.
  6. ^ [1] ←Page #975 (51st page of article) First ¶, first line.
  7. ^ [1] ←Page #975 (51st page of article) First ¶, 4th line.
  8. ^ [1] ←Page #973 (49th page of article) §C. & Page #974 (50th page of article) Figure 31 & Page #976 (52nd page of article) Table 29.
  9. ^ [1] ←Page #974 (50th page of article) Figure 31 & Page #977 (53rd page of article) Table 30.
  10. ^ [1] ←Page #974 (50th page of article) Figure 31 & Page #977 (53rd page of article) Table 30.
  11. ^ [1] ←Page #974 (50th page of article) Figure 31 & Page #977 (53rd page of article) Table 30.
  12. ^ [1] ←Page #974 (50th page of article) Figure 31 & Page #977 (53rd page of article) Table 30.
  13. ^ [1] ←Page #978 (54th page of article) §D & Page #980 (56th page of article) Figure 33 & Page #981 (57th page of article) Table 32.
  14. ^ [1] ←Page #978 (54th page of article) §D & Page #980 (56th page of article) Figure 33 & Page #981 (57th page of article) Table 32.
  15. ^ [1] ←Page #980 (56th page of article) Scheme 52.
  16. ^ [1] ←Page #982 (58th page of article) §G & Page #983 (59th page of article) Figure 36 & Page #984 (60th page of article) Table 35.
  17. ^ [1] ←Page #979 (55th page of article) Table 31.
  18. ^ [1] ←Page #981 (57th page of article) §E & Page #982 (58th page of article) Table 33.
  19. ^ [1] ←Page #982 (58th page of article) 3rd ¶, lines 2, 5 & 6.
  20. ^ [1] ←Page #982 (58th page of article) §F, Table 34 & Figure 35.
  21. ^ [1] ←Page #984 (60th page of article) §H, Figure 37 & Page #985 (61st page of article) Table 36.
  22. ^ [1] ←Page #984 (60th page of article) Scheme 56.
  23. ^ [1] ←Page #986 (62nd page of article) §I, Table 37 & Scheme 58
  24. ^ [1] ←Page #1,014 (90th page of article) §VIII, A. Figure 59.
  25. ^ [1] ←Page #1,016 (92nd page of article) Figure 60.
  26. ^ [18] ←Page #31, §3.2. ¶3, 15th & 16th lines, final sentence.
  27. ^ [1] ←Page #927 (3rd page of article) second ¶. Lines seven — fifteen.
  28. ^ [1] ←Page #987 (63rd page of article) §IV, Figure 39 & Page #988 (64th page of article) Table 38.
  29. ^ [1] ←Page #987 (63rd page of article) Figure 40, Page #988 (64th page of article) §B & Page #989 (65th page of article) Table 39.
  30. ^ [1] ←Page #987 (63rd page of article) Figure 41, Page #989 (65th page of article) §C & Page #990 (66th page of article) Table 40.
  31. ^ [1] ←Page #988 (64th page of article) Figure 42, Page #990 (66th page of article) §2 & Page #992 (68th page of article) Table 41.
  32. ^ [1] ←Page #988 (64th page of article) Figure 43, Page #992 (68th page of article) §3 & Table 42.
  33. ^ [1] ←Page #993 (69th page of article) §V. ¶2. Fourth line. First sentence.
  34. ^ [1] ←Page #993 (69th page of article) §V, Figure 46 & Table 43.
  35. ^ [1] ←Page #995 (71st page of article) Figure 47 & Page #997 (73rd page of article) Table 44.
  36. ^ [1] ←Page #997 (73rd page of article) §C, Page #998 (74th page of article) Figure 48 & Page #1,000 Table 45.
  37. ^ [1] ←Page #1,000 (76th page of article) §D, Page #1,001 (77th page of article) Figure 49 & Page #1,005 (81st page of article) Table 46.
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