Robertson D W, Lacefield W B, Bloomquist W, Pfeifer W, Simon R L, Cohen M L
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285.
J Med Chem. 1992 Jan 24;35(2):310-9. doi: 10.1021/jm00080a016.
Antagonists of 5HT3 receptors are clinically effective in treating nausea and emesis associated with certain oncolytic drugs, including cisplatin. Moreover, these agents may be useful in pharmacological management of several central nervous system disorders, including anxiety, schizophrenia, dementia, and substance abuse. Our studies on aroyltropanamides led to the discovery that dihydrobenzofuranyl esters and amides are potent 5HT3 receptor antagonists. Simple benzoyl derivatives of tropine and 3 alpha-aminotropane possessed weak 5HT3 receptor antagonist activity, as judged by blockade of bradycardia produced by iv injection of serotonin (5HT) to anesthetized rats. Within this series, use of benzofuran-7-carboxamide as the aroyl moiety led to a substantial increase of 5HT3 receptor affinity. The optimal 5HT3 receptor antagonist identified via extensive SAR studies was endo-5-chloro-2,3-dihydro-2,2-dimethyl-N-(8-methyl-8-azabicyclo[3.2.1]oc t- 3-yl)-7-benzofurancarboxamide (Z)-2-butenedioate (zatosetron maleate). The 7-carbamyl regiochemistry, dimethyl substitution, chloro substituent, and endo stereochemistry were all crucial elements of the SAR. Zatosetron maleate was a potent antagonist of 5HT-induced bradycardia in rats (ED50 = 0.86 micrograms/kg i.v.). Low oral doses of zatosetron (30 micrograms/kg) produced long-lasting antagonism of 5HT3 receptors, as evidenced by blockade of 5HT-induced bradycardia for longer than 6 h in rats. Moreover, this compound did not produce hemodynamic effects after i.v. administration to rats, nor did it block carbamylcholine-induced bradycardia in doses that markedly blocked 5HT3 receptors. Thus, zatosetron is a potent, selective, orally effective 5HT3 receptor antagonist with a long duration of action in rats.
5HT3受体拮抗剂在临床上可有效治疗与某些溶瘤药物（包括顺铂）相关的恶心和呕吐。此外，这些药物可能有助于多种中枢神经系统疾病的药物治疗，包括焦虑症、精神分裂症、痴呆症和药物滥用。我们对芳酰托品酰胺的研究发现，二氢苯并呋喃酯和酰胺是有效的5HT3受体拮抗剂。通过静脉注射血清素（5HT）使麻醉大鼠产生心动过缓，经阻断实验判断，托品和3α-氨基托烷的简单苯甲酰衍生物具有较弱的5HT3受体拮抗剂活性。在该系列化合物中，使用苯并呋喃-7-甲酰胺作为芳酰部分可使5HT3受体亲和力大幅提高。通过广泛的构效关系研究确定的最佳5HT3受体拮抗剂是内-5-氯-2,3-二氢-2,2-二甲基-N-(8-甲基-8-氮杂双环[3.2.1]辛-3-基)-7-苯并呋喃甲酰胺(Z)-2-丁烯二酸酯（扎托司琼马来酸盐）。7-氨基甲酰基区域化学、二甲基取代、氯取代基和内型立体化学都是构效关系的关键要素。扎托司琼马来酸盐是大鼠中5HT诱导心动过缓的有效拮抗剂（静脉注射半数有效量=0.86微克/千克）。低口服剂量的扎托司琼（30微克/千克）可对5HT3受体产生持久拮抗作用，大鼠中5HT诱导的心动过缓被阻断超过6小时即证明了这一点。此外，该化合物静脉注射给大鼠后未产生血流动力学效应，在显著阻断5HT3受体的剂量下也未阻断氨甲酰胆碱诱导的心动过缓。因此，扎托司琼是一种有效的、选择性的、口服有效的5HT3受体拮抗剂，在大鼠中作用持续时间长。
