The synthesis of bivalent 2β-carbomethoxy-3β-(3,4-dichlorophenyl)-8-heterobicyclo[3.2.1]octanes as probes for proximal binding sites on the dopamine and serotonin transporters

Peter C. Meltzer, Olga Kryatova, Duy Phong Pham-Huu, Patrick Donovan, Aaron Janowsky

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

3-Aryltropanes have been widely explored for potential medications for remediation of cocaine abuse. Research has focused predominantly on 8-azatropanes and it is now well recognized that these compounds can be designed to manifest varied selectivity and potency for inhibition of the dopamine, serotonin, and norepinephrine uptake systems. We had reported that the 8-nitrogen atom present in the 3-aryltropanes is not essential for tropanes to bind to monoamine uptake systems. We demonstrated that compounds in which the amine had been exchanged for an ether or a thioether retained binding potency and selectivity. We have now designed bivalent compounds in which two tropane moieties are linked by an intervening chain. These 8-homo- and 8-heterotropane bivalent compounds allowed a search for adjacent tropane binding sites on the DAT as well as a further exploration of whether the binding sites for 8-azatropanes are the same as those for other 8-heterotropanes. A comparison of these compounds with their progenitor tropanes cast into doubt the existence of proximal binding sites on the DAT, and offered support for the existence of different binding sites for the 8-azatropanes compared with 8-oxa- and 8-thiatropanes. Indeed, 8-aza bivalent tropanes inhibited DAT with potency about 10-fold lower (DAT: IC50 = 31 nM) than their monovalent counterparts. Furthermore, bivalent ligands in which one or both of the tropanes was devoid of an amine suffered a further loss of inhibitory potency. We conclude that it is unlikely that there exist two tropane binding sites in close proximity to one another on either the DAT or SERT.

Original languageEnglish (US)
Pages (from-to)1832-1841
Number of pages10
JournalBioorganic and Medicinal Chemistry
Volume16
Issue number4
DOIs
StatePublished - Feb 15 2008
Externally publishedYes

Fingerprint

Octanes
Tropanes
Serotonin Plasma Membrane Transport Proteins
Dopamine Plasma Membrane Transport Proteins
Binding Sites
Amines
Cocaine-Related Disorders
Sulfides
Remediation
Cocaine
Ether
Inhibitory Concentration 50
Dopamine
Serotonin
Norepinephrine
Nitrogen
Ligands
Atoms

Keywords

  • Bivalent ligands
  • Cocaine medications
  • Monoamine transporter ligands

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Organic Chemistry
  • Drug Discovery
  • Pharmaceutical Science
  • Medicine(all)

Cite this

The synthesis of bivalent 2β-carbomethoxy-3β-(3,4-dichlorophenyl)-8-heterobicyclo[3.2.1]octanes as probes for proximal binding sites on the dopamine and serotonin transporters. / Meltzer, Peter C.; Kryatova, Olga; Pham-Huu, Duy Phong; Donovan, Patrick; Janowsky, Aaron.

In: Bioorganic and Medicinal Chemistry, Vol. 16, No. 4, 15.02.2008, p. 1832-1841.

Research output: Contribution to journalArticle

@article{217aebec4d8c4e87848a61d187f7c518,
title = "The synthesis of bivalent 2β-carbomethoxy-3β-(3,4-dichlorophenyl)-8-heterobicyclo[3.2.1]octanes as probes for proximal binding sites on the dopamine and serotonin transporters",
abstract = "3-Aryltropanes have been widely explored for potential medications for remediation of cocaine abuse. Research has focused predominantly on 8-azatropanes and it is now well recognized that these compounds can be designed to manifest varied selectivity and potency for inhibition of the dopamine, serotonin, and norepinephrine uptake systems. We had reported that the 8-nitrogen atom present in the 3-aryltropanes is not essential for tropanes to bind to monoamine uptake systems. We demonstrated that compounds in which the amine had been exchanged for an ether or a thioether retained binding potency and selectivity. We have now designed bivalent compounds in which two tropane moieties are linked by an intervening chain. These 8-homo- and 8-heterotropane bivalent compounds allowed a search for adjacent tropane binding sites on the DAT as well as a further exploration of whether the binding sites for 8-azatropanes are the same as those for other 8-heterotropanes. A comparison of these compounds with their progenitor tropanes cast into doubt the existence of proximal binding sites on the DAT, and offered support for the existence of different binding sites for the 8-azatropanes compared with 8-oxa- and 8-thiatropanes. Indeed, 8-aza bivalent tropanes inhibited DAT with potency about 10-fold lower (DAT: IC50 = 31 nM) than their monovalent counterparts. Furthermore, bivalent ligands in which one or both of the tropanes was devoid of an amine suffered a further loss of inhibitory potency. We conclude that it is unlikely that there exist two tropane binding sites in close proximity to one another on either the DAT or SERT.",
keywords = "Bivalent ligands, Cocaine medications, Monoamine transporter ligands",
author = "Meltzer, {Peter C.} and Olga Kryatova and Pham-Huu, {Duy Phong} and Patrick Donovan and Aaron Janowsky",
year = "2008",
month = "2",
day = "15",
doi = "10.1016/j.bmc.2007.11.009",
language = "English (US)",
volume = "16",
pages = "1832--1841",
journal = "Bioorganic and Medicinal Chemistry",
issn = "0968-0896",
publisher = "Elsevier Limited",
number = "4",

}

TY - JOUR

T1 - The synthesis of bivalent 2β-carbomethoxy-3β-(3,4-dichlorophenyl)-8-heterobicyclo[3.2.1]octanes as probes for proximal binding sites on the dopamine and serotonin transporters

AU - Meltzer, Peter C.

AU - Kryatova, Olga

AU - Pham-Huu, Duy Phong

AU - Donovan, Patrick

AU - Janowsky, Aaron

PY - 2008/2/15

Y1 - 2008/2/15

N2 - 3-Aryltropanes have been widely explored for potential medications for remediation of cocaine abuse. Research has focused predominantly on 8-azatropanes and it is now well recognized that these compounds can be designed to manifest varied selectivity and potency for inhibition of the dopamine, serotonin, and norepinephrine uptake systems. We had reported that the 8-nitrogen atom present in the 3-aryltropanes is not essential for tropanes to bind to monoamine uptake systems. We demonstrated that compounds in which the amine had been exchanged for an ether or a thioether retained binding potency and selectivity. We have now designed bivalent compounds in which two tropane moieties are linked by an intervening chain. These 8-homo- and 8-heterotropane bivalent compounds allowed a search for adjacent tropane binding sites on the DAT as well as a further exploration of whether the binding sites for 8-azatropanes are the same as those for other 8-heterotropanes. A comparison of these compounds with their progenitor tropanes cast into doubt the existence of proximal binding sites on the DAT, and offered support for the existence of different binding sites for the 8-azatropanes compared with 8-oxa- and 8-thiatropanes. Indeed, 8-aza bivalent tropanes inhibited DAT with potency about 10-fold lower (DAT: IC50 = 31 nM) than their monovalent counterparts. Furthermore, bivalent ligands in which one or both of the tropanes was devoid of an amine suffered a further loss of inhibitory potency. We conclude that it is unlikely that there exist two tropane binding sites in close proximity to one another on either the DAT or SERT.

AB - 3-Aryltropanes have been widely explored for potential medications for remediation of cocaine abuse. Research has focused predominantly on 8-azatropanes and it is now well recognized that these compounds can be designed to manifest varied selectivity and potency for inhibition of the dopamine, serotonin, and norepinephrine uptake systems. We had reported that the 8-nitrogen atom present in the 3-aryltropanes is not essential for tropanes to bind to monoamine uptake systems. We demonstrated that compounds in which the amine had been exchanged for an ether or a thioether retained binding potency and selectivity. We have now designed bivalent compounds in which two tropane moieties are linked by an intervening chain. These 8-homo- and 8-heterotropane bivalent compounds allowed a search for adjacent tropane binding sites on the DAT as well as a further exploration of whether the binding sites for 8-azatropanes are the same as those for other 8-heterotropanes. A comparison of these compounds with their progenitor tropanes cast into doubt the existence of proximal binding sites on the DAT, and offered support for the existence of different binding sites for the 8-azatropanes compared with 8-oxa- and 8-thiatropanes. Indeed, 8-aza bivalent tropanes inhibited DAT with potency about 10-fold lower (DAT: IC50 = 31 nM) than their monovalent counterparts. Furthermore, bivalent ligands in which one or both of the tropanes was devoid of an amine suffered a further loss of inhibitory potency. We conclude that it is unlikely that there exist two tropane binding sites in close proximity to one another on either the DAT or SERT.

KW - Bivalent ligands

KW - Cocaine medications

KW - Monoamine transporter ligands

UR - http://www.scopus.com/inward/record.url?scp=38949169202&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=38949169202&partnerID=8YFLogxK

U2 - 10.1016/j.bmc.2007.11.009

DO - 10.1016/j.bmc.2007.11.009

M3 - Article

C2 - 18053732

AN - SCOPUS:38949169202

VL - 16

SP - 1832

EP - 1841

JO - Bioorganic and Medicinal Chemistry

JF - Bioorganic and Medicinal Chemistry

SN - 0968-0896

IS - 4

ER -