A new 5-HT3 receptor ligand. II. Structure-activity analysis of 5-HT3 receptor agonist action in the gut.
Several modified 2-piperazinyl benzoxazole derivatives, which exhibit an agonistic effect on gastrointestinal motility, were synthesized and their effects on the contraction of guinea-pig ileum were examined. The quaternary piperazinyl benzoxazole structure has a restricted conformation and stereostructure compared to those of the other 5-HT3 receptor agonists, serotonin and meta-chlorophenylbiguanide. The mutual positions of the aromatic ring, nitrogen atom and terminal amine are considered to form the pharmacophore of the 5-HT3 receptor agonist in the gut. In the serotonin-evoked reflex bradycardia [Bezold-Jarisch (B-J) reflex] inhibition test using rats the B-J reflex-inducing ratio was different for each synthesized compound. These results suggest that, in these 5-HT3 receptor agonists, the substituents of the benzoxazole ring influence the B-J reflex-inducing activity in rats.
Yamada
M
M
Pharmaceutical Research Center, Meiji Seika Kaisha, Yokohama, Japan.
Sato
Y
Y
Kobayashi
K
K
Konno
F
F
Soneda
T
T
Watanabe
T
T
D000818:Animals; D001583:Benzoxazoles / Q000737:chemistry* / Q000494:pharmacology; D018360:Crystallography, X-Ray; D008297:Male; D008958:Models, Molecular; D010879:Piperazines / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000187:drug effects; D044406:Receptors, Serotonin, 5-HT3; D017366:Serotonin Receptor Agonists / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D001583:Benzoxazoles; C108245:CP 2289; D010879:Piperazines; D011985:Receptors, Serotonin; D044406:Receptors, Serotonin, 5-HT3; D017366:Serotonin Receptor Agonists