2-[(2,3-dihydro-1H-indol-1-yl)methyl]melatonin analogues: a novel class of MT2-selective melatonin receptor antagonists.

A novel series of 2-[(2,3-dihydro-1H-indol-1-yl)methyl]melatonin analogues has been prepared to probe the steric and electronic properties of the binding pocket of the MT2 receptor accommodating the “out-of-plane” substituent of MT2-selective antagonists. The acetamide (6b) bearing an usubstituted indoline moiety displayed an excellent binding affinity and selectivity toward the MT2-subtype (MT2, Ki = 1 nM; MT1, Ki = 115 nM), behaving as a competitive antagonist. 5-Me, 5-OMe, 5-Br, 6-NH2, and 6-NO2 substitution of the indoline moiety reduced both MT2 affinity and selectivity, indicating that hydrophobic interactions play a decisive role in binding the out-of-plane substituent. The cyclobutanecarboxamide (6e) showed a biphasic binding pattern at MT2 receptors, indicating the presence of two MT2 binding sites, a high affinity (Ki = 1 pM) and a low affinity (Ki = 148 nM), while MT1 binding affinity was very low (Ki = 1.4 μM). Functional analysis of 6e revealed it to be an antagonist at MT1 receptors and a pa...