Side Chain Substituted Indolealkyl Amides as Potent Melatonin Receptor Ligands

Melatonin (N-acetyl-5-methoxytryptamine) modulates circadian rhythms and sleep-wake cycles, primarily via activation of the MT1 and MT2 melatonin receptors which exhibit distinct pharmacological profiles. The MT1/MT2 melatonin receptor ligand, luzindole (LUZ), delays re-entrainment of running wheel activity following an advance of dark onset via the MT1, and exerts antidepressant-like effects via the MT2 melatonin receptor. Our goal is to design and synthesize novel analogues with at least 50-fold selectivity for either MT1 or MT2 and a pharmacological profile on each receptor compatible with that of LUZ (ei., antagonist/inverse agonists at MT1; antagonist/partial agonists at MT2) to potentially mimic distinct receptor-mediated behaviors. Our strategy is to assess structure-activity relationships of indolealkyl amides to identify optimal functional groups that yield a more defined efficacy. A series of b-methyl, b,b-dimethyl and a-methyl C3-side chain functionalized indolealkyl amides, incorporating C2-Me...