Novel antagonists of 5-HT3 receptors. Synthesis and biological evaluation of piperazinylquinoxaline derivatives.
A series of piperazinylquinoxalines has been synthesized and studied as 5-HT3 receptor antagonists in different preparations. Antagonism to 5-HT in the longitudinal muscle of the guinea pig ileum was particularly prominent in cyanoquinoxaline derivatives with an alkyl substitutuent on the piperazine moiety. The pA2 of some selected compounds against the 5-HT3 agonist 2-methyl-5HT in the guinea pig ileum was in the range of tropisetron or ondansetron, and one of them, 7e, was more potent than these reference compounds by approximately 2 or 3 orders of magnitude. However, these compounds were markedly less potent than either tropisetron or ondansetron as displacers of 3H-BRL 43694 binding to rat cortical membranes or as antagonists of the Bezold-Jarisch reflex in rats. Piperazinylcyanoquinoxalines represent a new class of 5-HT3 antagonists with a selective effect on guinea pig peripheral receptors.
Monge
A
A
Department Química Orgánica y CIFA, Universidad de Navarra, Pamplona, Spain.
Palop
J A
JA
Del Castillo
J C
JC
Calderó
J M
JM
Roca
J
J
Romero
G
G
Del Río
J
J
Lasheras
B
B
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006168:Guinea Pigs; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D010879:Piperazines / Q000138:chemical synthesis* / Q000494:pharmacology*; D011810:Quinoxalines / Q000138:chemical synthesis* / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D012702:Serotonin Antagonists; D013329:Structure-Activity Relationship
D010879:Piperazines; D011810:Quinoxalines; D012702:Serotonin Antagonists