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The 5‐HT 4 receptor antagonist ML10375 inhibits the constitutive activity of human 5‐HT 4(c) receptor
Author(s) -
Blondel Olivier,
Gastineau Monique,
Langlois Michel,
Fischmeister Rodolphe
Publication year - 1998
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0702163
Subject(s) - adenylyl cyclase , inverse agonist , receptor , 5 ht4 receptor , agonist , receptor antagonist , medicine , intrinsic activity , endocrinology , protease activated receptor 2 , antagonist , pertussis toxin , enzyme linked receptor , chemistry , 5 ht receptor , 5 ht5a receptor , competitive antagonist , g protein , biology , serotonin , biochemistry
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 ‐3,5‐dimethylpiperidino)ethyl 4‐amino‐5‐chloro‐2‐methoxybenzoate (ML10375) at 1 μ M completely abolished the 5‐HT (1 μ M )‐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 effect of ML10375 on basal adenylyl cyclase activity was not modified 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. British Journal of Pharmacology (1998) 125 , 595–597; doi: 10.1038/sj.bjp.0702163