The novel N-substituted benztropine analog GA2-50 possesses pharmacokinetic and pharmacodynamic profiles favorable for a candidate substitute medication for cocaine abuse.
- Citation:
- Othman, A. A., A. H. Newman, and N. D. Eddington, "The novel N-substituted benztropine analog GA2-50 possesses pharmacokinetic and pharmacodynamic profiles favorable for a candidate substitute medication for cocaine abuse.", Journal of pharmaceutical sciences, vol. 97, issue 12, pp. 5453-70, 2008 Dec.
Abstract:
GA2-50 is a novel N-substituted benztropine analog with improved potency and selectivity for the dopamine transporter. The pharmacokinetic and pharmacodynamic properties of GA2-50 were characterized as a part of its preclinical evaluation as a substitute medication for cocaine abuse. In vitro transport and metabolism studies as well as pharmacokinetic studies in rats were conducted. Effect of GA2-50 on the extracelluar nucleus accumbens (NAc) dopamine levels and on cocaine's induced dopamine elevation was evaluated using intracerebral microdialysis. GA2-50 showed high transcellular permeability despite being a P-glycoprotein substrate. GA2-50 was a substrate of human CYP2D6, CYP2C19, CYP2E1, rat CYP2C11, CYP2D1, CYP3A1, and CYP1A2; with low intrinsic clearance values. In vivo, GA2-50 showed high brain uptake (R(i) approximately 10), large volume of distribution (V(ss) = 37 L/kg), and long elimination half-life (t((1/2)) = 19 h). GA2-50 resulted in 1.6- and 2.7-fold dopamine elevation at the 5 and 10 mg/kg i.v. doses. Dopamine elevation induced by GA2-50 was significantly reduced, slower and longer lasting than previously observed for cocaine. GA2-50 had no significant effect on cocaine's induced dopamine elevation upon simultaneous administration. Results from the present study indicate that GA2-50 possesses several attributes sought after for a substitute medication for cocaine abuse.
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