JZ-IV-10: Difference between revisions

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{{Drugbox

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| verifiedrevid = ~~449578252~~

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| verifiedrevid = 451228350

| IUPAC_name = (+)-2-([(3R,4S)-1-methyl-4-(4-chlorophenyl)piperidin-3-yl]methylthio)-N-isopropylacetamide

| image = ~~16e_chemical_structure~~.png

| image = JZ-IV-10 chemical structure.png

| width = 200

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| metabolism =

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| CAS_number_Ref = {{cascite|changed|CAS}}

| CAS_number =

| CAS_number = 807342-16-1

| UNII_Ref = {{fdacite|correct|FDA}}

| UNII = GYT6ACY5JL

| ATC_prefix =

| ATC_suffix =

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| DrugBank_Ref = {{drugbankcite|correct|drugbank}}

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| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}

| ChemSpiderID = 9466185

| C=18 | H=27 | Cl=1 | N=2 | O=1 | S=1

| smiles = Clc1ccc(cc1)[C@H]2CCN(C)C[C@@H]2CSCC(=O)NC(C)C

| molecular_weight = 354.937 g/mol

| StdInChI_Ref = {{stdinchicite|changed|chemspider}}

| smiles = c2cc(Cl)ccc2C1CCN(C)CC1CSCC(=O)NC(C)C

| StdInChI = 1S/C18H27ClN2OS/c1-13(2)20-18(22)12-23-11-15-10-21(3)9-8-17(15)14-4-6-16(19)7-5-14/h4-7,13,15,17H,8-12H2,1-3H3,(H,20,22)/t15-,17-/m1/s1

| StdInChIKey_Ref = {{stdinchicite|changed|chemspider}}

| StdInChIKey = GPNABXAHBDYHFE-NVXWUHKLSA-N

}}

'''JZ-IV-10''' is a [[piperidine]] derivative related to [[nocaine]] which is a highly potent [[triple reuptake inhibitor]] (SNDRI).<ref>{{Cite patent|WO|2005041875}}</ref> The eugeroic [[modafinil]], was used as a lead to fuel these compounds' discovery [http://pubs.acs.org/doi/suppl/10.1021/jm040117o/suppl_file/jm040117o_s.pdf (J. Zhou, et al. 2004)].<ref>{{Cite pmid|15537337}}</ref> Although it turns out that the [[Quantitative structure-activity relationship|QSAR]] of the pharmacophoric elements do not appear to be strongly similar. The other isomers were also prepared, although they are weaker than the R,S probes invented in the current study [http://pubs.acs.org/doi/suppl/10.1021/jm050694s/suppl_file/jm050694ssi20050823_061156.pdf (R. He, et al. 2005)].<ref>{{Cite pmid|16335921}}</ref>

'''JZ-IV-10''' is a [[piperidine]] derivative related to [[cocaine]] which acts as a highly potent [[serotonin–norepinephrine–dopamine reuptake inhibitor]] (also called SNDRI, or triple reuptake inhibitor).<ref>{{cite patent|country=WO|number=2005041875|title=Dopamine-, norepinephrine- and serotonin- transporter- selective heterocyclic compounds and their therapeutic applications|pubdate=2005-05-12|assign=[[Georgetown University]]|inventor1-last= Kozikowski|inventor1-first=Alan P.

{| class="wikitable"

|inventor2-last=Zhou|inventor2-first=Jia}}</ref> The [[eugeroic]] [[modafinil]] was used as a lead to fuel this compound's discovery.<ref>{{cite journal | vauthors = Zhou J, He R, Johnson KM, Ye Y, Kozikowski AP | title = Piperidine-based nocaine/modafinil hybrid ligands as highly potent monoamine transporter inhibitors: efficient drug discovery by rational lead hybridization | journal = Journal of Medicinal Chemistry | volume = 47 | issue = 24 | pages = 5821–4 | date = November 2004 | pmid = 15537337 | pmc = 1395211 | doi = 10.1021/jm040117o }}</ref><ref>{{cite journal | vauthors = He R, Kurome T, Giberson KM, Johnson KM, Kozikowski AP | title = Further structure-activity relationship studies of piperidine-based monoamine transporter inhibitors: effects of piperidine ring stereochemistry on potency. Identification of norepinephrine transporter selective ligands and broad-spectrum transporter inhibitors | journal = Journal of Medicinal Chemistry | volume = 48 | issue = 25 | pages = 7970–9 | date = December 2005 | pmid = 16335921 | doi = 10.1021/jm050694s }}</ref>

|JZ #||R||X||Y||[3H]NE||[3H]DA||[3H]5HT

|-

|III-82 → ?||rowspan=2|Me||colspan=2|-CO2H||70.2 → ?||121.2 → ?||269.9 → ?

|-

|III-48 → III-59||rowspan=2|Ester||rowspan=2|OMe||25 → 53||80 → 231||208 → 809

|-

|IV-22 → ?||H||10 → 31.1||114 → 107.8||170 → 774.9

|-

|IV-25 → IV-37||Me||rowspan=7|Amide||rowspan=2|NH2||39 → 178||159 → 209</td><td>557 → 5790</td>

|-

|||H||10 → 31.1||114 → 107.8||170 → 774.9

|-

|III-62 → III-85||rowspan=10|Me||HNOH||15 → 12||85 → 55||227 → 1795

|-

|IV-5 → IV-14||HNMe||25 → 86||13 → 164||110 → 2033

|-

|IV-23 → IV-27||-NMe2||27 → 1249||116 → 2884||88 → 924

|-

|IV-10 → IV-15||NHPri||0.8 → 20||1.0 → 248||1.1 → 473

|-

|IV-7 → IV-16||-N(CH2)5||0.68 → 460||83 → 379||4.5 → 825

|-

|III-84 → IV-34||rowspan=4|H2||OH||0.94 → 42||16 → 12||158 → 2183

|-

|IV-35 → IV-36||OMe||6 → 25||50 → 15||191 → 469

|-

|III-86 → III-91||OAc||3.6 → 29||35 → 9||57 → 87

|-

|III-87 → III-90||OBz||4.5 → 18||68 → 32||6.7 → 199

|-

|IV-17 → IV-21||colspan=2|Het||31.5 → 217.6||125.7 → 1,653||220.9 → 1,079

|}

[[Image:Triplemode.gif|center]]

[[Image:JZ-IV-17 structure.png|left|100px]]

Upon "treatment" of the ligands with ([[hydrogen peroxide|H2O2]] + AcOH) the sulfur atom is oxidized. The resultant molecules then lose most of their potency. This is not a major concern though (c.f. [[cimetidine]], [[ranitidine]]). Little has been reported about the SAR of modafinil itself, and it is interesting to consider how these new findings could be applied retrospectively. The NRI selective molecules were employed as brain imaging agents to unravel details about the NE transporter.<ref>{{Cite pmid|16621532}}</ref> NRIs are important probes, but they do not function as robust reinforcers.<ref>{{Cite pmid|16213110}}</ref>

==~~References~~==

== See also ==

* [[1-Methyl-3-propyl-4-(p-chlorophenyl)piperidine]]

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* [[N,O-Dimethyl-4-(2-naphthyl)piperidine-3-carboxylate]]

* [[Nocaine]]

== References ==

⚫

[[Category:Stimulants]]

[[Category:~~Amides~~]]

[[Category:Carboxamides]]

[[Category:~~Piperidines~~]]

[[Category:4-Phenylpiperidines]]

[[Category:~~Organochlorides~~]]

[[Category:Chloroarenes]]

[[Category:Serotonin–norepinephrine–dopamine reuptake inhibitors]]