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 for labelling the 5-HT4 serotoninergic receptors. Previous works in our laboratories established the bioisosteric equivalency of the indole heterocycle and naphthalene in a series of melatonin receptor ligands. Based on this knowledge we designed new analogues of GR 113808 by introducing two bioisosteric modifications: firstly, the indole ring was replaced by a naphthalene one and secondly, the ester linkage was replaced by an amide group. Compound 8 emerged within this novel series as it displayed high and selective affinity 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 undergoing further pharmacological evaluation. (C) 2000 Editions scientifiques et medicales Elsevier SAS.