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 MT(2) receptor accommodating the "out-of-plane" substituent of MT(2)-selective antagonists. The acetamide (6b) bearing an usubstituted indoline moiety displayed an excellent binding affinity and selectivity toward the MT(2)-subtype (MT(2), K(i) = 1 nM; MT(1), K(i) = 115 nM), behaving as a competitive antagonist. 5-Me, 5-OMe, 5-Br, 6-NH(2), and 6-NO(2) substitution of the indoline moiety reduced both MT(2) 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 MT(2) receptors, indicating the presence of two MT(2) binding sites, a high affinity (K(i) = 1 pM) and a low affinity (K(i) = 148 nM), while MT(1) binding affinity was very low (K(i) = 1.4 microM). Functional analysis of 6e revealed it to be an antagonist at MT(1) receptors and a partial agonist, at best, at MT(2) receptors.