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.
