Pharmacological properties of quinoxaline derivatives as a new class of 5-HT3 receptor antagonists.
The pharmacological profile of five quinoxaline derivatives, a new class of 5HT3 receptor antagonists, is reported in the present study. All of the new compounds antagonized the effect of the selective 5-HT3 receptor agonist 2-methyl-5-HT in the isolated longitudinal muscle-myenteric plexus preparation (LMMP) of guinea-pig ileum. One of them, VC-605) was approximately three orders of magnitude more potent than ondansetron. In binding studies to 5-HT3 receptors from rat cerebral cortex membranes only VC-605 showed an affinity comparable to ondansetron. In the isolated rat oesophageal tunica muscularis mucosae preparation the new compounds, like 2-methyl-5-HT, only produced relaxation of the contraction induced by carbachol at high concentrations. In vivo, the quinoxaline derivatives were weak antagonists of the bradycardia response to 5-HT in the anesthetized rat. The quinoxaline derivatives, in particular VC-501 and VC-603, prevented retches and vomiting induced by 2-methyl-5-HT and cis-platinum in the ferret. The new compounds also enhanced the gastric emptying of solids in rats. The results obtained are probably indicative of the suggested species- and tissue-dependent differences in 5-HT3 receptor subtypes. The high potency and selectivity of one of the new quinoxaline derivatives, VC-605, at 5-HT3 receptors of guinea-pig ileum is remarkable. VC-605 may be a useful tool for further characterizing this possible 5-HT3 receptor subtype.
Lasheras
B
B
Department of Pharmacology, School of Pharmacy, University of Navarra, Spain.
Berjón
A
A
Montañés
R
R
Roca
J
J
Romero
G
G
Ramírez
M J
MJ
Del Río
J
J
D000818:Animals; D000932:Antiemetics / Q000494:pharmacology; D004947:Esophagus / Q000187:drug effects; D005260:Female; D005289:Ferrets; D005746:Gastric Emptying / Q000187:drug effects; D006168:Guinea Pigs; D008297:Male; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009197:Myenteric Plexus / Q000187:drug effects; D011810:Quinoxalines / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism*; D012018:Reflex / Q000187:drug effects; D012702:Serotonin Antagonists / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity
D000932:Antiemetics; D011810:Quinoxalines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists