Behavioral pharmacology of AR-A000002,
a novel, selective 5-hydroxytryptamine(1B) antagonist

by
Hudzik TJ, Yanek M, Porrey T, Evenden J,
Paronis C, Mastrangelo M, Ryan C, Ross S, Stenfors C.
AstraZeneca R & D, Wilmington,
Massachusetts, USA.
thomas.hudzik@astrazeneca.com
J Pharmacol Exp Ther. 2003 Mar;304(3):1072-84


ABSTRACT

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.
TCAs
SSRIs
5-HT1
5-HT2
5-HT3
5-HT1a
5-HT2c
Anpirtoline
Eltoprazine
Zolmitriptan
Knockout mice
5-HT2c/5-HT2b
5-HT1a v 5-HT1b
SSRIs and 5-HT1b
MDMA and 5-HT1a
MDMA and 5-HT1b
5-HT1b and reward
5-HT1b and anxiety
Aggression and serotonin
5-HT-moduline, serotonin and mood
5-HT1b inverse agonists as antidepressants


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