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Solid-phase Synthesis of [4.4] Spirocyclic Oximes
Published on: February 6, 2019
Scouting new sigma receptor ligands: Synthesis, pharmacological evaluation and molecular modeling of
Silvia Franchini1, Umberto Maria Battisti1, Adolfo Prandi1
1Dipartimento di Scienze della Vita, Università di Modena e Reggio Emilia, Via Campi 103, 41125 Modena, Italy.
Abstract:
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 σ1R (pKiσ1 = 9.13; σ1/σ2 = 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 σ1R. Docking studies were performed on the theoretical σ1R homology model. The present work represents a new starting point for the design of more potent and selective σ1R ligands.
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