Design of subtype selective melatonin receptor agonists and antagonists

Studies of the physiological actions of melatonin have been hindered by the lack of specific, potent and subtype selective agonists and antagonists. I n the present study, we describe the utility of a melanophore cell line fro m Xenopus laevis for exploring structure-activity relationships among novel melatonin analogues and report a novel MT2-selective agonist (IIK7) and MT 2-selective receptor antagonist (K185). IIK7 is a potent melatonin receptor agonist in the melanophore model, and in NIH3T3 cells expressing human mt( 1) and MT2 receptor subtypes. In radioligand binding experiments IIK7 is 90 -fold selective for the MT2 subtype. K185 is devoid of agonist activity, bu t acts as a competitive melatonin antagonist in melanophores. A low concent ration (10(-9) M) antagonizes melatonin inhibition of forskolin stimulation of cyclic AMP in NIH3T3 cells expressing human MT2 receptors, but has no e ffect in cells expressing mt(1) receptors. In binding assays, K185 is 140-f old selective for the MT2 subtype. (C) Inra/Elsevier, Paris.