TY - JOUR T1 - Preclinical Pharmacology and Pharmacokinetics of AZD3783, a Selective 5-HT1B Receptor Antagonist JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.110.174433 SP - jpet.110.174433 AU - Minli Zhang AU - Diansong Zhou AU - Yi Wang AU - Donna L Maier AU - Daniel V Widzowski AU - Cynthia D Sobotka-Briner AU - Becky J Brockel AU - William M Potts AU - Ashok B Shenvi AU - Peter R Bernstein AU - M Edward Pierson Y1 - 2011/01/01 UR - http://jpet.aspetjournals.org/content/early/2011/08/08/jpet.110.174433.abstract N2 - The preclinical pharmacology and pharmacokinetic properties of AZD3783, a potent 5-hydroxytryptamine 1B (5-HT1B) receptor antagonist, were characterized as part of translational pharmacokinetic/pharmacodynamic hypothesis testing in human clinical trials. The affinity of AZD3783 to the 5-HT1B receptor was measured in vitro using membrane preparations containing recombinant human or guinea pig 5-HT1B receptors and in native guinea pig brain tissue. In vivo antagonist potency of AZD3783 for the 5HT1B receptor was investigated by measuring the blockade of 5-HT1B agonist-induced guinea pig hypothermia. The anxiolytic-like potency was assessed using the suppression of separation-induced vocalization in guinea pig pups. The affinity of AZD3783 for human and guinea pig 5-HT1B receptor (Ki = 12.5 and 11.1 nM, respectively) was similar to unbound plasma EC50 values for guinea pig receptor occupancy (11 nM) and reduction of agonist-induced-hypothermia (18 nM) in guinea pig. Active doses of AZD3783 in the hypothermia assay were similar to doses that reduced separation-induced vocalization in guinea pig pups. AZD3783 demonstrated favorable pharmacokinetic properties. The predicted pharmacokinetic parameters (CL = 6.5 mL/min/kg; Vdss = 6.4 L/kg) were within 2-fold of the values observed in healthy male volunteers following a 20 mg single oral dose. This investigation presents a direct link between AZD3783 in vitro affinity and in vivo receptor occupancy to preclinical disease model efficacy. Together with predicted human pharmacokinetic properties, we have provided a model for the quantitative translational pharmacology of AZD3783 that increases confidence in the optimal human receptor occupancy required for antidepressant and anxiolytic effects in patients. ER -