Population Pharmacokinetics, Brain Distribution, and Pharmacodynamics of 2nd Generation Dopamine Transporter Selective Benztropine Analogs Developed as Potential Substitute Therapeutics for Treatment of Cocaine Abuse

Abstract

A second generation of N-substituted 3a-[bis(40-fluorophenyl)methoxy]- tropanes (GA 1–69, JHW 005 and JHW 013) binds with high affinity to the dopamine transporter (DAT) and are highly selective toward DAT compared to muscarinic receptor binding (M1). The objective of this study was to characterize brain distribution, pharmacokinetics, and pharmacodynamics [extracellular brain dopamine (DA) levels] of three novel N-substituted benztropine (BZT) analogs in male Sprague–Dawley rats. The BZT analogs displayed a higher distribution (Vd¼8.69–34.3 vs. 0.9 L/kg) along with longer elimination (t1/2: 4.1–5.4 vs. 0.5 h) than previously reported for cocaine. Brain-toplasma partition coefficients were 1.3–2.5 vs. 2.1 for cocaine. The effect of the BZT analogs on extracellular brain (DA) levels ranged from minimal effects (GA 1–69) to several fold elevation ( 850% of basal DA for JHW 013) at the highest dose evaluated. PK/PD analysis of exposure–response data resulted in lower IC50 values for the BZT analogs compared to cocaine indicating their higher potency to inhibit DA reuptake (0.1–0.3 vs. 0.7 mg/L). These BZT analogs possess significantly different PK and PD profiles as compared to cocaine suggesting that further evaluation as cocaine abuse therapeutics is warranted. 2007 Wiley-Liss, Inc. and the American Pharmacists Keywords: pharmacokinetics; pharmacodynamics; dopamine; benztropine analogs; cocaine.