Reassessing the melatonin pharmacophore—Enantiomeric resolution, pharmacological activity, structure analysis, and molecular modeling of a constrained chiral melatonin analogue

• Published in: Bioorganic & medicinal chemistry Vol. 14; no. 10; pp. 3383 - 3391
• Main Authors: Rivara, Silvia, Diamantini, Giuseppe, Di Giacomo, Barbara, Lamba, Doriano, Gatti, Giuseppe, Lucini, Valeria, Pannacci, Marilou, Mor, Marco, Spadoni, Gilberto, Tarzia, Giorgio
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 15.05.2006; Elsevier Science
• Subjects: 3T3 Cells; Animals; Binding, Competitive - drug effects; Biological and medical sciences; Conformational analysis; Crystallography, X-Ray; Enantiomeric resolution; Magnetic Resonance Spectroscopy; Medical sciences; Melatonin; Melatonin - analogs & derivatives; Melatonin - chemistry; Melatonin - pharmacology; Mice; Models, Molecular; Molecular modeling; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems; Pharmacology. Drug treatments; Pharmacophore model; Receptors, Melatonin - metabolism; Stereoisomerism; Structure-Activity Relationship; X-ray crystal structure; Enantiomeric resolution; Melatonin; X-ray crystal structure; Pharmacophore model; Molecular modeling; Conformational analysis; Separation; Aminoacid derivative hormone; Liquid chromatography; NMR spectrometry; Crystallography; In vitro; Modeling; Biological activity; Optical resolution; Enantiomer; Absolute configuration; Molecular model; Affinity; MT2 melatonin receptor; MT1 melatonin receptor; Structural analysis; Crystalline structure
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2005.12.053

3-(Acetylaminomethyl)-2-(ethoxycarbonyl)-6-methoxy-1,3,4,5-tetrahydrobenzo[ cd]indole ( 2) is a rigid melatonin analogue that as a racemate displays about the same affinity and intrinsic activity of melatonin ( 1) in in vitro experiments. We report here the resolution of the racemate by preparative medium pressure liquid chromatography (MPLC) and the X-ray determination of the R absolute configuration of the (−)-enantiomer. The two enantiomers were separately tested as MT 1 and MT 2 ligands, and the (+)-( S)- 2 showed a potency comparable to that of melatonin and about three orders of magnitude greater than that of its enantiomer. The information obtained by crystallographic analysis and NMR studies about the conformational preference for 2 and by the pharmacological characterization of ( R)- 2 and ( S)- 2 was employed in a molecular modeling study, aimed at reassessing the melatonin receptor pharmacophore model for agonist compounds. Chiral enantioselective agonists reported in the literature were also included in the study.