Synthesis and preliminary pharmacological results on new naphthalene derivatives as 5-HT4 receptor ligands

The indole derivative GR 113808 is currently used as the reference Ligand f or labelling the 5-HT4 serotoninergic receptors. Previous works in our labo ratories established the bioisosteric equivalency of the indole heterocycle and naphthalene in a series of melatonin receptor ligands. Based on this k nowledge we designed new analogues of GR 113808 by introducing two bioisost eric modifications: firstly, the indole ring was replaced by a naphthalene one and secondly, the ester linkage was replaced by an amide group. Compoun d 8 emerged within this novel series as it displayed high and selective aff inity at 5-HT4 receptors (Ki 5-HT4 = 6 nM, Ki 5-HT3 = 100 nM, Ki values at other 5-HT receptors were higher than 1 000 nM). Compound 8 is currently un dergoing further pharmacological evaluation. (C) 2000 Editions scientifique s et medicales Elsevier SAS.