Synthesis and pharmacological evaluation of 1,2,3,4-tetrahydropyrazino[1,2-a]indole and 2-[(phenylmethylamino)methyl]-1H-indole analogues as novel melatoninergic ligands

Two novel series of melatonin-derived compounds have been synthesized and pharmacologically evaluated at the MT1 and MT2 subtypes of melatonin receptors. Compounds 12b–c are non-selective high-affinity MT1 and MT2 receptor ligands (Ki = 7–11 nM). Compound 12b had little intrinsic activity at the MT1 receptor and no intrinsic activity at the MT2 receptor. Compound 20d displayed the highest MT2 binding affinity (Ki = 2 nM) and moderate selectivity toward the MT2 subtype (Ki MT1/MT2 ratio = 8) behaving as MT2 antagonist and MT1 agonist (IC50 = 112 pM). The findings help define SARs around the positions 1 and 2 of melatonin with respect to binding affinity, MT2 selectivity, and intrinsic activity.

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