Yoshida N, Omoya H, Kato S, Ito T
Exploratory Research Laboratories, Dainippon Pharmaceutical Co., Ltd., Suita/Osaka, Japan.
Eur J Pharmacol. 1992 Jun 17;216(3):435-40. doi: 10.1016/0014-2999(92)90442-7.
The serotonin 5-HT3 receptor antagonist effects of DAT-582, the (R) enantiomer of AS-5370 ((+/-)-N-[1-methyl-4-(3-methyl-benzyl)hexahydro-1H-1,4-diazepin-6- yl]-1H- indazole-3-carboxamide dihydrochloride), and its antipode were compared with those of AS-5370 and existing 5-HT3 receptor antagonists. In anesthetized rats, DAT-582 antagonized 2-methyl-5-HT-induced bradycardia with an ED50 value of 0.25 microgram/kg i.v., whereas the (S) enantiomer was without effect even at 1000 micrograms/kg i.v. In antagonizing the bradycardia, DAT-582 was as potent as granisetron, slightly more potent than AS-5370, and 2, 5 and 18 times more potent than ondansetron, ICS 205-903 and renzapride, respectively, although it was less potent than zacopride. DAT-582 inhibited cisplatin (10 mg/kg i.v.)-induced emesis in ferrets with an ED50 value of 3.2 micrograms/kg i.v. twice. The antiemetic activity of DAT-582 was more potent than that of the existing 5-HT3 receptor antagonists examined, except zacopride. In contrast, the (S) enantiomer had little effect at 1000 micrograms/kg i.v. twice. In isolated guinea-pig ileum, DAT-582 inhibited 5-HT-induced contractions with an IC50 value of 91 nM, whereas the (S) enantiomer hardly inhibited them even at 1000 nM. These results suggest that DAT-582, the (R) enantiomer of AS-5370, potently and selectively blocks 5-HT3 receptors.
比较了AS-5370（（±）-N-[1-甲基-4-（3-甲基苄基）六氢-1H-1,4-二氮杂卓-6-基]-1H-吲唑-3-甲酰胺二盐酸盐）的（R）对映体DAT-582及其对映体与AS-5370和现有5-HT3受体拮抗剂的5-羟色胺5-HT3受体拮抗作用。在麻醉大鼠中，DAT-582拮抗2-甲基-5-HT诱导的心动过缓，静脉注射ED50值为0.25微克/千克，而（S）对映体即使在静脉注射1000微克/千克时也无作用。在拮抗心动过缓方面，DAT-582与格拉司琼效力相当，比AS-5370稍强，分别比昂丹司琼、ICS 205-903和瑞扎曲普坦强2倍、5倍和18倍，尽管其效力低于扎考必利。DAT-582抑制雪貂顺铂（静脉注射10毫克/千克）诱导的呕吐，静脉注射ED50值为3.2微克/千克，给药两次。DAT-582的止吐活性比所检测的现有5-HT3受体拮抗剂（扎考必利除外）更强。相比之下，（S）对映体在静脉注射1000微克/千克、给药两次时几乎没有作用。在离体豚鼠回肠中，DAT-582抑制5-HT诱导的收缩，IC50值为91 nM，而（S）对映体即使在1000 nM时也几乎不抑制。这些结果表明，AS-5370的（R）对映体DAT-582能有效且选择性地阻断5-HT3受体。
