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 MT(1) and MT(2) subtypes of melatonin receptors. Compounds 12b-c are non-selective high-affinity MT(1) and MT(2) receptor ligands (K(i)=7-11 nM). Compound 12b had little intrinsic activity at the MT(1) receptor and no intrinsic activity at the MT(2) receptor. Compound 20d displayed the highest MT(2) binding affinity (K(i)=2 nM) and moderate selectivity toward the MT(2) subtype (K(i) MT(1)/MT(2) ratio=8) behaving as MT(2) antagonist and MT(1) agonist (IC(50)=112 pM). The findings help define SARs around the positions 1 and 2 of melatonin with respect to binding affinity, MT(2) selectivity, and intrinsic activity.