RT Journal Article SR Electronic T1 Preclinical Pharmacology and Pharmacokinetics of AZD3783, a Selective 5-Hydroxytryptamine 1B Receptor Antagonist JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 567 OP 578 DO 10.1124/jpet.110.174433 VO 339 IS 2 A1 Minli Zhang A1 Diansong Zhou A1 Yi Wang A1 Donna L. Maier A1 Daniel V. Widzowski A1 Cynthia D. Sobotka-Briner A1 Becky J. Brockel A1 William M. Potts A1 Ashok B. Shenvi A1 Peter R. Bernstein A1 M. Edward Pierson YR 2011 UL http://jpet.aspetjournals.org/content/339/2/567.abstract AB The preclinical pharmacology and pharmacokinetic properties of (2R)-6-methoxy-8-(4-methylpiperazin-1-yl)-N-(4-morpholin-4-ylphenyl)chromane-2-carboxamide (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 by 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 (total plasma clearance, 6.5 ml/min/kg; steady-state volume of distribution, 6.4 l/kg) were within 2-fold of the values observed in healthy male volunteers after a single 20-mg 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.