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Synthesis, dopamine transporter affinity, dopamine uptake inhibition, and locomotor stimulant activity of 2-substituted 3 beta-phenyltropane derivatives.
J Med Chem. 1997 Mar 14; 40(6):858-63.JM

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.

Authors+Show Affiliations

Department of Chemistry, University of New Orleans, Louisiana 70148, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

9083474

Citation

Xu, L, et al. "Synthesis, Dopamine Transporter Affinity, Dopamine Uptake Inhibition, and Locomotor Stimulant Activity of 2-substituted 3 Beta-phenyltropane Derivatives." Journal of Medicinal Chemistry, vol. 40, no. 6, 1997, pp. 858-63.
Xu L, Kelkar SV, Lomenzo SA, et al. Synthesis, dopamine transporter affinity, dopamine uptake inhibition, and locomotor stimulant activity of 2-substituted 3 beta-phenyltropane derivatives. J Med Chem. 1997;40(6):858-63.
Xu, L., Kelkar, S. V., Lomenzo, S. A., Izenwasser, S., Katz, J. L., Kline, R. H., & Trudell, M. L. (1997). Synthesis, dopamine transporter affinity, dopamine uptake inhibition, and locomotor stimulant activity of 2-substituted 3 beta-phenyltropane derivatives. Journal of Medicinal Chemistry, 40(6), 858-63.
Xu L, et al. Synthesis, Dopamine Transporter Affinity, Dopamine Uptake Inhibition, and Locomotor Stimulant Activity of 2-substituted 3 Beta-phenyltropane Derivatives. J Med Chem. 1997 Mar 14;40(6):858-63. PubMed PMID: 9083474.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Synthesis, dopamine transporter affinity, dopamine uptake inhibition, and locomotor stimulant activity of 2-substituted 3 beta-phenyltropane derivatives. AU - Xu,L, AU - Kelkar,S V, AU - Lomenzo,S A, AU - Izenwasser,S, AU - Katz,J L, AU - Kline,R H, AU - Trudell,M L, PY - 1997/3/14/pubmed PY - 1997/3/14/medline PY - 1997/3/14/entrez SP - 858 EP - 63 JF - Journal of medicinal chemistry JO - J. Med. Chem. VL - 40 IS - 6 N2 - 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. SN - 0022-2623 UR - https://www.unboundmedicine.com/medline/citation/9083474/Synthesis_dopamine_transporter_affinity_dopamine_uptake_inhibition_and_locomotor_stimulant_activity_of_2_substituted_3_beta_phenyltropane_derivatives_ L2 - https://dx.doi.org/10.1021/jm960739c DB - PRIME DP - Unbound Medicine ER -