Population pharmacokinetics, brain distribution, and pharmacodynamics of 2nd generation dopamine transporter selective benztropine analogs developed as potential substitute therapeutics for treatment of cocaine abuse (original) (raw)

A second generation of N-substituted 3a-[bis(4 0 -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 (M 1 ). 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 (V d ¼ 8.69-34.3 vs. 0.9 L/kg) along with longer elimination (t 1/2 : 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 IC 50 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. ß