Felcisetrag stimulates 5-HT4-serotonin receptors in the human atrium

Felcisetrag (methyl 4-[[4-[[(2-propan-2-yl-1H-benzimidazole-4-carbonyl)-amino]-methyl]-piperidin-1-yl]methyl]piperidine-1-carboxylate, TD-8954, TAK-954) has a structural formula with similarity to serotonin. It is one of the most potent compounds to bind to recombinant human 5-HT₄-serotonin receptors. We noted that felcisetrag raised force of contraction in left atrial preparations (LA) and beating rate in right atrial preparations (RA) from mice with cardiac-specific overexpression of the human 5-HT₄ receptors (5-HT₄-TG) but was inactive in LA and RA from adult wild type mouse hearts (WT). When felcisetrag had increased force of contraction in LA or beating rate in RA of 5-HT₄-TG, GR125487, a 5-HT₄ receptor antagonist, reduced force of contraction and beating rate. Felcisetrag raised force of contraction only in the presence of cilostamide in human right atrial preparations (HAP) obtained from adult patients during open heart surgery due to severe coronary heart disease. These positive inotropic effects of felcisetrag in HAP were attenuated by 1 µM GR125487. In the presence of cilostamide, 100 nM felcisetrag exerted positive inotropic effects that were increased further by 1 µM serotonin. When 1 µM serotonin had raised force of contraction, additionally applied 100 nM felcisetrag reduced force of contraction in HAP. These data suggest that felcisetrag can act as an agonist as well as an antagonist at human 5-HT₄ receptors in the mammalian heart.

5-HT4-serotonin receptors; Felcisetrag; Human atrium; Mouse atrium; Transgenic mice.