The 5-HT 4 receptor antagonist ML10375 inhibits the constitutive activity of human 5-HT 4(c) receptor 1,2,4

Olivier Blondel (1) , Monique Gastineau (1) , Michel Langlois (2) , Rodolphe Fischmeister (1)

1 CARPAT - Signalisation et physiopathologie cardiovasculaire
2 BioCIS - Biomolécules : Conception, Isolement, Synthèse

Transient expression in COS-7 cells of the recombinant human 5-hydroxytryptamine (5-HT) h5-HT 4(c) receptor isoform led to constitutive activity of the receptor. The 5-HT 4 receptor antagonist 2-(cis-3,5dimethylpiperidino)ethyl 4-amino-5-chloro-2-methoxybenzoate (ML10375) at 1 mM completely abolished the 5-HT (1 mM)-mediated increase in adenylyl cyclase activity in COS-7 cells expressing the h5-HT 4(c) receptor. Moreover, ML10375 also reduced basal cAMP levels in cells over-expressing the receptor, even in the absence of agonist. The inhibitory eect of ML10375 on basal adenylyl cyclase activity was not modi®ed by pre-treatment of the cells with pertussis toxin, indicating that ML10375 acts through inactivation of spontaneously active h5-HT 4(c) receptors rather than through a G i /G o regulatory pathway. We conclude that ML10375 acts as an inverse agonist on the h5-HT 4(c) receptor.

Keywords: Human; serotonin 5-HT 4 receptors; inverse agonist; ML10375

Domains: Cardiology and cardiovascular system; Pharmacology

Olivier Blondel, Monique Gastineau, Michel Langlois, Rodolphe Fischmeister. The 5-HT 4 receptor antagonist ML10375 inhibits the constitutive activity of human 5-HT 4(c) receptor 1,2,4. British Journal of Pharmacology, 1998, 125 (4), pp.595-597. ⟨10.1038/sj.bjp.0702163⟩. ⟨hal-03616997⟩