STRUCTURAL REQUIREMENTS AT THE MELATONIN RECEPTOR

1 High affinity, specific binding sites for the pineal hormone, melato nin (5-methoxy N-acetyltryptamine) can be detected in chick brain memb ranes by use of the radiolabelled agonist, 2-[I-125]-iodomelatonin (2- [I-125]-aMT). 2 The affinity of a number of analogues of melatonin at the 2-[I-125]-aMT binding site was determined and compared with an ana lysis of their electronic structure and significant quantitative relat ionships obtained. 3 The best correlations indicated that binding affi nity was correlated with Delta E, the difference between the frontier orbital energies, and Q(N)H, the electron density in the highest occup ied molecular orbital of the side-chain nitrogen atom. 4 These finding s suggest that ligand binding may involve hydrogen bonding between the 5-methoxy and amide moieties of melatonin and complementary amino aci d residues, and charge transfer interactions between the indole ring o f melatonin and an aromatic amino acid in the receptor binding site. 5 A molecular model of a putative binding site is proposed based on the predicted amino acid sequence of the cloned Xenopus laevis melanophor e melatonin receptor and the quantitative structure-affinity relations hips observed in the present study.