Application of the bridgehead fragments for the design of conformationally restricted melatonin analogues

Conformationally constrained analogues of the hormone melatonin with a side chain incorporated into the bicyclic bridgehead core were synthesized based on the homology modeling and molecular docking studies performed for the MT2 melatonin receptor. The methoxy-indole derivative fused with exo-N-acetamino-substituted bicyclo[2.2.2]octane was found to possess nanomolar MT2 receptor affinity.

Analogues of endogenous hormone melatonin with a side chain incorporated into the bicyclic bridgehead cores were synthesized (left panel). The experimentally determined binding affinity of methoxy-indole derivative fused with exo-N-acetamino-substituted bicyclo[2.2.2]octane confirmed the molecular docking predictions (right panel).Figure optionsDownload as PowerPoint slideHighlights
► Bridgehead moieties were used for conformational restriction of melatonin side chain.
► All compounds were synthesized by Fisher indolization of the bridgehead ketones.
► Bicyclo[2.2.2]octane analogue was found to possess nanomolar MT2 affinity.