Velusetrag (TD-5108) 是一种具有口服活性，有效和选择性的血清素 5-HT4 受体 (5-HT4R) 激动剂，pKi 为 7.7。Velusetrag 对 5-HT2A 和 5-HT2B 受体没有亲和力 (Ki>10 μM)。Velusetrag 可用于胃肠道疾病和帕金森病的研究。
Velusetrag (TD-5108) is an orally active, potent and selective agonist of serotonin 5-HT4 receptor (5-HT4R), with a pKi of 7.7. Velusetrag exhibits no affinity (Ki>10 μM) for 5-HT2A and 5-HT2B receptors. Velusetrag can be used for the research of gastrointestinal diseases and Parkinson’s disease[1][2][3][4][5].
Velusetrag (10 pM-100 μM) concentration-dependently increases the cAMP in HEK-293 cells stably transfected with the h5-HT4(c) receptor, with a pEC50 of 8.3[1].Velusetrag (100 pM-1 μM) produces concentration-dependent contraction of the guinea pig colonic longitudinal muscle/myenteric plexus (LMMP), with a pEC50 of 7.9[1].Velusetrag (0.001-10 μM) produces a concentration-dependent relaxation of the carbachol (3 μM)-precontracted rat esophagus, with a pEC50 of 7.9[1].
Velusetrag (3 mg/kg; a single i.p.) significantly improves the facilitation of contextual fear extinction in PD mice[3].Velusetrag (3 mg/kg; a single i.p.) increases hippocampal cAMP levels in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice[3].Velusetrag (0.003-3 mg/kg; a single s.c.) increases colonic transit in a dose-dependent manner and reduces the time taken for excretion of the dye in guinea pigs[2].Velusetrag (0.003-1 mg/kg; a single i.v.) dose-dependently increases inter-crystal distance, consistent with relaxation of the oesophagus in rats[2].
[1]. Smith JAM, et, al. The in vitro pharmacological profile of TD-5108, a selective 5-HT(4) receptor agonist with high intrinsic activity. Naunyn Schmiedebergs Arch Pharmacol. 2008 Jul;378(1):125-37.
[2]. Beattie DT, et, al. The in vivo gastrointestinal activity of TD-5108, a selective 5-HT(4) receptor agonist with high intrinsic activity. Naunyn Schmiedebergs Arch Pharmacol. 2008 Jul;378(1):139-47.
[3]. Ishii T, et, al. Serotonin 5-HT 4 Receptor Agonists Improve Facilitation of Contextual Fear Extinction in an MPTP-Induced Mouse Model of Parkinson’s Disease. Int J Mol Sci. 2019 Oct 26;20(21):5340.
[4]. Kuo B, et al. Velusetrag accelerates gastric emptying in subjects with gastroparesis: a multicentre, double-blind, randomised, placebo-controlled, phase 2 study. Aliment Pharmacol Ther. 2021;53(10):1090-1097.
[5]. Goldberg M, et al. Clinical trial: the efficacy and tolerability of velusetrag, a selective 5-HT4 agonist with high intrinsic activity, in chronic idiopathic constipation - a 4-week, randomized, double-blind, placebo-controlled, dose-response study. Aliment Pharmacol Ther. 2010;32(9):1102-1112.
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