Scouting new sigma receptor ligands: Synthesis, pharmacological evaluation and molecular modeling of 1,3-dioxolane-based structures and derivatives.

Herein we report the synthesis and biological activity of new sigma receptor (σR) ligands obtained by combining different substituted five-membered heterocyclic rings with appropriate σR pharmacophoric amines. Radioligand binding assay, performed on guinea pig brain membranes, identified 25b (1-(1,4-dioxaspiro[4.5]decan-2-ylmethyl)-4-benzylpiperazine) as the most interesting compound of the series, displaying high affinity and selectivity for σ 1 R (pK i σ 1 = 9.13; σ 1 /σ 2 = 47). The ability of 25b to modulate the analgesic effect of the κ agonist (−)-U-50,488H and μ agonist morphine was evaluated in vivo by radiant heat tail-flick test. It exhibited anti-opioid effects on both κ and μ receptor-mediated analgesia, suggesting an agonistic behavior at σ 1 R. Docking studies were performed on the theoretical σ 1 R homology model. The present work represents a new starting point for the design of more potent and selective σ 1 R ligands. [ABSTRACT FROM AUTHOR]