Vol. 304, Issue 3, 1072-1084, March 2003

Behavioral Pharmacology of AR-A000002, a Novel, Selective 5-Hydroxytryptamine_1B Antagonist

T. J. Hudzik, M. Yanek, T. Porrey, J. Evenden, C. Paronis, M. Mastrangelo, C. Ryan, S. Ross and C. Stenfors

AstraZeneca R & D, Wilmington, Massachusetts (T.H., M.Y., M.M., J.E.); AstraZeneca R & D, Sodertalje, Sweden (C.R., S. R., C.S.); and Harvard Medical School, McLean Hospital, Belmont, Massachusetts (C.P.)

The present review summarizes the behavioral pharmacology conducted to profile the anxiolytic and antidepressant potential of the selective 5-hydroxytryptamine (HT)_1B antagonist (R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzamide (AR-A000002). AR-A000002 functions as a 5-HT_1B antagonist in vivo, which was shown by the antagonism of the discriminative stimulus effects in the guinea pig of the 5-HT_1B agonist 3-(N-methylpyrrolidin-2R-ylmethyl)-5-(3-nitropyrid-2-ylamino)-lH-indole (CP135,807). Anxiolytic activity of AR-A000002 was demonstrated in the separation-induced vocalization paradigm in guinea pig pups, and in a suppressed responding procedure in pigeons and guinea pigs, but only a weak trend was noted in a suppressed responding procedure in squirrel monkeys. Antidepressant efficacy was shown in a number of paradigms. In pigeons and guinea pigs responding under a differential reinforcement of low rates schedule of reinforcement (DRL), AR-A000002 increased the number of reinforcers earned without altering the number of responses made. In guinea pigs trained under a response duration differentiation paradigm, AR-A000002 increased mean lever-press duration. Finally, AR-A000002 was shown to block escape failures in guinea pigs submitted to a learned helplessness paradigm. Taken together, these data suggest utility for 5-HT_1B antagonists in the treatment of both anxiety and affective disorders.