SYNTHESIS AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF NOVEL NAPHTHALENIC AND BIOISOSTERIC RELATED AMIDIC DERIVATIVES AS MELATONIN RECEPTOR LIGANDS

A previous paper reported the synthesis of melatonin receptor ligands. In order to complete the structure-activity relationships and to obta in antagonists to the melatonin receptor, a new series of naphthalenic analogues of melatonin have been synthesized. Modifications include d eletion of the 7-methoxy group, replacement of the ethylene moiety, re placement of the amidic function by bioisosteres, and replacement of t he naphthalenic nucleus by other bicyclic rings. Almost all the struct ural modifications lead to decreased affinity for the melatonin recept or. However, the N-n propyl urea derivative (27) is a very potent liga nd at this receptor (pK(i) = 14.3). Most interestingly deletion of the methoxy group resulted in the first antagonist in this series. This m olecule, compound 12, or N-[2-(1-naphthyl)ethyl]cyclobutyl carboxamide has been selected for preclinical development. (C) 1998 Published by Elsevier Science Ltd. All rights reserved.