Synthesis, Dopamine Transporter Affinity, Dopamine Uptake Inhibition, and Locomotor Stimulant Activity of 2-Substituted 3β-Phenyltropane Derivatives
- 1 March 1997
- journal article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 40 (6), 858-863
- https://doi.org/10.1021/jm960739c
Abstract
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 (Ki = 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/Ki = 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.Keywords
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