A series of N-(2-phenylbenzofuran-3-yl) ethyl amide and N-(2-arylalkylbenzofuran-3-yl) ethyl amide derivatives were synthesized and evaluated as melatonin receptor ligands. The affinity of each compound for the two MT(1) and MT(2) melatonin receptor subtypes was determined by binding studies using 2-[(125)I]iodomelatonin on human embryonic kidney cell line HEK293 membrane homogenates. The intrinsic activity of the most interesting compounds was evaluated on the [(35)S]GTPgammaS binding assay. Introduction of a 2-phenyl substituent in the C-2 benzofuran position leads to an agonist compound, 10q, which binds more strongly than melatonin itself to both MT(1) and MT(2) subtypes. On the other hand, a 2-benzyl group in the same position allows MT(2) antagonist selective ligands to be obtained. The MT(2) selectivity and antagonist potency can be modulated with suitable modifications on the N-acyl and benzyl substituents, and the most selective compounds 10c and 19 show affinity ratios of 123 and 192, respectively, and bind to the MT(2) subtype similarly to melatonin itself (0.1 nM). Nevertheless, 10c acts as an MT(1) and MT(2) antagonist, whereas 19 is a partial agonist.

Tetrahydronaphthalenic analogues of melatonin have been synthesized and evaluated as melatonin receptor ligands. Introduction of a phenyl substituent in the 3-position of the tetraline ring allows to obtain MT(2) selective ligands. Activity and MT(2) selectivity can be modulated with suitable modifications of the N-acyl substituent. The (+)-(RR)-cis enantiomer of the N-[2-(7-methoxy-3-phenyl-1,2,3,4-tetrahydro-naphthalen-1-yl)ethyl]cyclobutyl carboxamide (14) is one of the most MT(2) selective ligands described until now and behaves as an antagonist.