Synthesis and biological properties of new 2β-alkyl- and 2β-aryl-3- (substituted phenyl)tropane derivatives

Stereochemical effect of C-3 on affinity and selectivity for neuronal dopamine and serotonin transporters

Alan P. Kozikowski, Gian Luca Araldi, K. R C Prakash, Mei Zhang, Kenneth M. Johnson

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

In our efforts to identify molecules that might act as cocaine antagonists or cocaine partial agonists, we have been involved in efforts to further elucidate the nature of cocaine's binding to the dopamine transporter (DAT) through strategic modifications of its structure. In the case of the substituent located at the 2-position of the tropane ring, studies have revealed the ability of the transporter to accommodate groups of diverse structure, including ester, ketone, alkyl, alkenyl, heterocyclic, and aryl substituents, without loss of DAT binding affinity. In the present study, we report our results pertaining to the ability of the DAT to accommodate the WIN-type structures possessing alkyl or aryl groups at the 2-position and which adopt either a chair or a boat conformation of the tropane ring. Moreover, we discuss the influence of the stereochemistry of these compounds in their selectivity for the DAT versus the serotonin transporter (5HTT). Additionally, we point out the importance of using K(i) values rather than IC50 values when making such comparisons of transporter selectivity. One of the most interesting compounds identified in the present work is a 2,3- diaryltropane 22 in a boat conformation that is highly selective (69-fold) for the DAT over the-5HTT. The ability to prepare this compound as well as related structures by our oxidopyridinium betaine-based dipolar cycloaddition strategy further underscores the versatility of this particular chemical approach to the preparation of diverse tropane analogues. The use of the optically pure olefin p-tolyl vinyl sulfoxide as the dipolarophile in this reaction allows access to these novel tropanes in nonracemic form.

Original languageEnglish (US)
Pages (from-to)4973-4982
Number of pages10
JournalJournal of Medicinal Chemistry
Volume41
Issue number25
DOIs
StatePublished - Dec 3 1998

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Tropanes
Serotonin Plasma Membrane Transport Proteins
Dopamine Plasma Membrane Transport Proteins
Derivatives
Cocaine
sulfoxide
Ships
Boats
Conformations
Betaine
Stereochemistry
Cycloaddition
Cycloaddition Reaction
Alkenes
Ketones
Inhibitory Concentration 50
Esters
Molecules

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Synthesis and biological properties of new 2β-alkyl- and 2β-aryl-3- (substituted phenyl)tropane derivatives : Stereochemical effect of C-3 on affinity and selectivity for neuronal dopamine and serotonin transporters. / Kozikowski, Alan P.; Araldi, Gian Luca; Prakash, K. R C; Zhang, Mei; Johnson, Kenneth M.

In: Journal of Medicinal Chemistry, Vol. 41, No. 25, 03.12.1998, p. 4973-4982.

Research output: Contribution to journalArticle

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