Cohen M L, Bloomquist W, Schaus J M, Thompson D C, Susemichel A D, Calligaro D A, Cohen I
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA.
J Pharmacol Exp Ther. 1996 Apr;277(1):97-104.
Although many 5-HT (serotonin, 5-hydroxytryptamine)(4) receptor antagonists have been described, none possess the requisite oral activity and duration of action for a clinically effective therapeutic agent. The present report identifies LY353433 (1-(1-methylethyl)-N-[2-[4-[tricyclo[3.3.1.1(3,7)]dec-1-ylcarbo nyl) amino]-1-piperidinyl]ethyl]-1H-indazole-3-carboxamide), an indazole amide, as a high affinity antagonist at the 5-HT(4) receptor in the rat esophagus. LY353433 (10(-8), 3 x 10(-8), 10(-7) M) inhibited 5-HT-induced relaxation of carbamylcholine-contracted esophagus with greater potency than cisapride or RS23597-190, a known 5-HT(4) receptor ligand. Furthermore, RS23597-190 possessed marked agonist activity as did cisapride, whereas LY353433 did not relax the rat esophagus in concentrations up to 10(-5) M. LY353433 (up to 10(-5) M) did not possess appreciable affinity for adrenergic, dopaminergic, histaminergic, muscarinic or GABAergic receptors and, thus, was a highly selective 5-HT(4) receptor antagonist. In addition, LY353433 only slowly associated with an dissociated from the 5-HT(4) receptor, an attribute that conferred long-lasting 5-HT(4) receptor antagonist activity, in contrast to RS23597-190, which rapidly dissociated from the 5-HT(4) receptor. LY353433 dose-dependently inhibited the 5-HT(4) receptor-mediated ex vivo relaxation in the rat esophagus after either i.v. (0.1, 0.3 and 1.0 mg/kg) or p.o. (0.1, 0.3, 1.0 and 3.0 mg/kg) administration. Furthermore, the p.o. to i.v. dose ratio was approximately one, suggesting that LY353433 was well absorbed with excellent pharmacodynamics in the rat. LY353433 (0.3 mg/kg p.o.) blocked esophageal 5-HT(4) receptors ex vivo through 6 hr after p.o. dosing with responses returning to control by 16 hr, indicative of long duration receptor blockade. Lastly, in rats LY353433 was exceptionally safe because acute doses up to 300 mg/kg p.o. did not result in either symptoms or deaths. Thus, LY353433 is a potent, selective, orally effective, long-acting and safe 5-HT(4) receptor antagonist that is highly suitable for clinical use.
尽管已经报道了许多5-羟色胺（血清素，5-羟色胺）（4）受体拮抗剂，但没有一种具备临床上有效治疗药物所需的口服活性和作用持续时间。本报告鉴定了吲唑酰胺LY353433（1-（1-甲基乙基）-N-[2-[4-[三环[3.3.1.1(3,7)]癸-1-基羰基）氨基]-1-哌啶基]乙基]-1H-吲唑-3-甲酰胺），它是大鼠食管中5-HT(4)受体的高亲和力拮抗剂。LY353433（10^(-8)、3×10^(-8)、10^(-7) M）抑制5-羟色胺诱导的氨甲酰胆碱收缩食管的松弛作用，其效力大于西沙必利或已知的5-HT(4)受体配体RS23597-190。此外，RS23597-190与西沙必利一样具有明显的激动剂活性，而LY353433在浓度高达10^(-5) M时不会使大鼠食管松弛。LY353433（高达10^(-5) M）对肾上腺素能、多巴胺能、组胺能、毒蕈碱能或GABA能受体没有明显亲和力，因此是一种高度选择性的5-HT(4)受体拮抗剂。此外，LY353433与5-HT(4)受体的结合和解离都很缓慢，这一特性赋予了其持久的5-HT(4)受体拮抗剂活性，与之形成对比的是，RS23597-190能迅速从5-HT(4)受体上解离。静脉注射（0.1、0.3和1.0 mg/kg）或口服（0.1、0.3、1.0和3.0 mg/kg）后，LY353433剂量依赖性地抑制大鼠食管中5-HT(4)受体介导的离体松弛。此外，口服与静脉注射的剂量比约为1，表明LY353433在大鼠体内吸收良好，药效学表现优异。口服给药0.3 mg/kg的LY353433在给药后6小时内离体阻断食管5-HT(4)受体，16小时后反应恢复到对照水平，表明受体阻断持续时间长。最后，在大鼠中LY353433异常安全，因为口服高达300 mg/kg的急性剂量既未导致症状也未导致死亡。因此，LY353433是一种强效、选择性、口服有效、长效且安全的5-HT(4)受体拮抗剂，非常适合临床使用。
