Design and Synthesis of Bivalent Ligands Targeting Human Melatonin Receptors

Design and Synthesis of Bivalent Ligands Targeting Human Melatonin Receptors

Melatonin is the principle hormone of the pineal gland and is believed to have a central role in the regulation of the mammalian circadian system. Many biological effects of melatonin are produced through activation of melatonin receptors. Both MT₁ and MT₂ receptors bind melatonin with high affinity. Luzindole is a competitive antagonist of melatonin that binds both MT₁ and MT₂ receptors. A key structural feature responsible for melatonin and luzindole binding include an indole ring and acetamido group. Recently, using computational models of MT1/MT2 our laboratory has identified an additional pocket in melatonin receptor which could be used to enhance receptor selectivity. Our goal is to create bivalent ligands to map melatonin receptor and identify structural clues to enhance potency and selectivity. Molecular dynamics (MD) based flexible docking was employed to screen a large library of compounds. A combination of FlexX (SYBYL, Tripos), MOE (Chemical Computing Group, Inc.), INSIGHT (Accelrys), and manual structure-guided docking were employed to map receptor ligand binding surfaces. From these results, mini libraries of compounds were synthesized. Using competitive 2-[¹²⁵I]-iodomelatonin binding to membranes of hMT₁ and hMT₂ melatonin receptors expressed in CHO cells, will verify binding for each receptor. Discovering selective melatonin receptor ligands will significantly advance studies on the mechanism(s) of action of melatonin and the potential for identification of new drug discovery targets.