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

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 MT1 and MT2 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.