Beattie D T, Armstrong S R, Shaw J P, Marquess D, Sandlund C, Smith J A M, Taylor J A, Humphrey P P A
Theravance, Inc., 901 Gateway Boulevard, South San Francisco, CA, 94080, USA.
Naunyn Schmiedebergs Arch Pharmacol. 2008 Jul;378(1):139-47. doi: 10.1007/s00210-008-0281-z. Epub 2008 Apr 12.
The in vivo preclinical pharmacodynamic profile of TD-5108, a selective 5-HT(4) receptor agonist with high intrinsic activity, was compared to that of the clinically studied gastrointestinal pro-kinetic agents, tegaserod, cisapride and mosapride. The activity of TD-5108 was evaluated in guinea pig colonic transit, rat oesophageal relaxation and dog gastrointestinal smooth muscle contractility models. Subcutaneous administration of TD-5108, tegaserod, cisapride and mosapride increased guinea pig colonic transit (rank order of potencies: TD-5108 > tegaserod > cisapride > mosapride). Following intravenous and intraduodenal dosing, TD-5108, tegaserod, cisapride and mosapride produced dose-dependent relaxation of the rat oesophagus. On a molar basis, TD-5108 was approximately twofold less potent than tegaserod following intravenous dosing but 6- or 86-fold more potent than cisapride or mosapride, respectively, and 9- or 18-fold more potent than tegaserod or cisapride, respectively, after intraduodenal administration. Orally dosed TD-5108 increased the contractility of the canine antrum, duodenum and jejunum with higher potency than tegaserod. The selective 5-HT(4) receptor agonist, TD-5108, demonstrates robust in vivo activity in the guinea pig, rat and dog gastrointestinal tracts.
将具有高内在活性的选择性5-HT(4)受体激动剂TD-5108的体内临床前药效学特征与临床研究的胃肠道促动力剂替加色罗、西沙必利和莫沙必利进行了比较。在豚鼠结肠转运、大鼠食管松弛和犬胃肠道平滑肌收缩模型中评估了TD-5108的活性。皮下注射TD-5108、替加色罗、西沙必利和莫沙必利可增加豚鼠结肠转运（效价顺序：TD-5108>替加色罗>西沙必利>莫沙必利）。静脉注射和十二指肠给药后，TD-5108、替加色罗、西沙必利和莫沙必利可使大鼠食管产生剂量依赖性松弛。以摩尔为基础，静脉给药后TD-5108的效价比替加色罗低约两倍，但分别比西沙必利或莫沙必利高6倍或86倍，十二指肠给药后分别比替加色罗或西沙必利高9倍或18倍。口服TD-5108可增加犬胃窦、十二指肠和空肠的收缩性，效价比替加色罗高。选择性5-HT(4)受体激动剂TD-5108在豚鼠、大鼠和犬的胃肠道中表现出强大的体内活性。
