Behavioral pharmacology of AR-A000002, a novel, selective 5-hydroxytryptamine(1B) antagonist.
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.
Hudzik
T J
TJ
AstraZeneca R & D, Wilmington, Massachusetts, USA. thomas.hudzik@astrazeneca.com
Yanek
M
M
Porrey
T
T
Evenden
J
J
Paronis
C
C
Mastrangelo
M
M
Ryan
C
C
Ross
S
S
Stenfors
C
C
D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D010856:Columbidae; D004193:Discrimination Learning / Q000187:drug effects*; D006168:Guinea Pigs; D006380:Helplessness, Learned; D008297:Male; D009025:Morpholines / Q000494:pharmacology*; D011930:Reaction Time; D044302:Receptor, Serotonin, 5-HT1B; D011985:Receptors, Serotonin / Q000378:metabolism*; D012453:Saimiri; D012702:Serotonin Antagonists / Q000494:pharmacology*; D014828:Vocalization, Animal / Q000187:drug effects*
D001549:Benzamides; D009025:Morpholines; C473209:N-(5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl)-4-morpholinobenzamide; D044302:Receptor, Serotonin, 5-HT1B; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists