Synthesis, dopamine transporter affinity, dopamine uptake inhibition, and locomotor stimulant activity of 2-substituted 3β-phenyltropane derivatives

Lifen Xu, Shreekrishna V. Kelkar, Stacey A. Lomenzo, Sari Izenwasser, Jonathan L. Katz, Richard H. Kline, Mark L. Trudell

Research output: Contribution to journalArticle

29 Scopus citations


A series of 2β-substituted 3β-phenyltropanes were synthesized as analogs of cocaine and tested in vitro for their ability to displace bound [3H]WIN 35,428 (2b) and inhibit dopamine uptake in rat caudate-putamen tissue. The analogs bound with high affinity (K(i) = 11-22 nM) to the dopamine transporter. Increased lipophilicity at the β-C(2)-position was found to lead to increased binding affinity and increased dopamine uptake potency. However, a direct correlation between clogP values and binding affinity and potency of uptake inhibition was not observed. The unsaturated ester 7 was found to possess weak dopamine uptake inhibition relative to the high binding affinity (IC50/K(i) = 10.2). In vivo measurement of stimulated locomotor activity and drug discrimination against cocaine (10 mg/kg, ip) with selected analogs (4, 6, and 7) demonstrated that the behavioral effects of these drugs were approximately equipotent with those of cocaine. The structure-activity relationships of this series of cocaine analogs supports a pharmacophore model in which lipophilic interactions between the β- C(2)position of 3β-phenyltropanes and the cocaine binding site on the dopamine transporter lead to enhanced potency while electrostatic interactions have a nonspecific effect.

Original languageEnglish (US)
Pages (from-to)858-863
Number of pages6
JournalJournal of Medicinal Chemistry
Issue number6
StatePublished - Mar 14 1997
Externally publishedYes


ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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