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  • Title: Synthesis, dopamine transporter affinity, dopamine uptake inhibition, and locomotor stimulant activity of 2-substituted 3 beta-phenyltropane derivatives.
    Author: Xu L, Kelkar SV, Lomenzo SA, Izenwasser S, Katz JL, Kline RH, Trudell ML.
    Journal: J Med Chem; 1997 Mar 14; 40(6):858-63. PubMed ID: 9083474.
    Abstract:
    A series of 2 beta-substituted 3 beta-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 beta-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 beta-C(2)-position of 3 beta-phenyltropanes and the cocaine binding site on the dopamine transporter lead to enhanced potency while electrostatic interactions have a nonspecific effect.
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