Benzoxazole derivatives as novel 5-HT3 receptor partial agonists in the gut.
A series of benzoxazoles with a nitrogen-containing heterocyclic substituent at the 2-position was prepared and evaluated for 5-HT3 partial agonist activity on isolated guinea pig ileum. The nature of the substituent at the 5-position of the benzoxazole ring affected the potency for the 5-HT3 receptor, and the 5-chloro derivatives showed increased potency and lowered intrinsic activity. 5-Chloro-7-methyl-2-(4-methyl-1-homopiperazinyl)benzoxazole (6v) exhibited a high binding affinity in the same range as that of the 5-HT3 antagonist granisetron, and its intrinsic activity was 12% of that of 5-HT. Compound 6v inhibited 5-HT-evoked diarrhea but did not prolong the transition time of glass beads in the normal distal colon even at a dose of 100 times the ED50 for diarrhea inhibition in mice. Compounds of this type are expected to be effective for the treatment of irritable bowel syndrome without the side effect of constipation.
Pharmaceutical Research Center, Meiji Seika Kaisha, 760 Morooka-Cho, Kohoku-ku, Yokohama 222, Japan.
Y
Y
Sato
M
M
Yamada
S
S
Yoshida
T
T
Soneda
M
M
Ishikawa
T
T
Nizato
K
K
Suzuki
F
F
Konno
D000818:Animals; D001583:Benzoxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000378:metabolism; D003106:Colon / Q000187:drug effects / Q000502:physiology; D003967:Diarrhea / Q000517:prevention & control; D005772:Gastrointestinal Transit / Q000187:drug effects; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects* / Q000502:physiology; D008297:Male; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000378:metabolism; D044406:Receptors, Serotonin, 5-HT3; D012018:Reflex / Q000187:drug effects; D017366:Serotonin Receptor Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D013329:Structure-Activity Relationship
C113643:5-chloro-7-methyl-2-(4-methyl-1-homopiperazinyl)benzoxazole; D001583:Benzoxazoles; D010879:Piperazines; D011985:Receptors, Serotonin; D044406:Receptors, Serotonin, 5-HT3; D017366:Serotonin Receptor Agonists