Sato Y, Yamada M, Yoshida S, Soneda T, Ishikawa M, Nizato T, Suzuki K, Konno F
Pharmaceutical Research Center, Meiji Seika Kaisha, 760 Morooka-Cho, Kohoku-ku, Yokohama 222, Japan.
J Med Chem. 1998 Jul 30;41(16):3015-21. doi: 10.1021/jm9801004.
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.
制备了一系列在2-位带有含氮杂环取代基的苯并恶唑，并在离体豚鼠回肠上评估其5-HT3部分激动剂活性。苯并恶唑环5-位取代基的性质影响5-HT3受体的活性，5-氯衍生物显示出活性增加和内在活性降低。5-氯-7-甲基-2-(4-甲基-1-高哌嗪基)苯并恶唑(6v)表现出与5-HT3拮抗剂格拉司琼相同范围内的高结合亲和力，其内在活性为5-HT的12%。化合物6v抑制5-HT引起的腹泻，但即使在抑制小鼠腹泻的ED50的100倍剂量下，也不会延长玻璃珠在正常远端结肠中的通过时间。这类化合物有望有效治疗肠易激综合征而无便秘副作用。
