Sigma-1 ligands: Tic-hydantoin as a key pharmacophore

Sigma-1 receptors are involved in numerous pathological dysfunctions and the synthesis of selective ligands is of interest. We identified a fused tetrahydroisoquinoline-hydantoin (Tic-hydantoin) structure with high affinity and selectivity for these receptors. We report here our efforts towards the pharmacomodulation of this substructure, the synthesis of 9 analogs with stereochemistry inversion, opening of isoquinoline ring, removal of isoquinoline nitrogen, replacement of isoquinoline by pyridine, of Tic-hydantoin moiety by quinazolinedione heterocycle. All these analogs provided a loss in the affinity for the sigma-1 receptor. The present work underlines the real importance of the Tic-hydantoin moiety for the obtainment of high affinity ligands.