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.
Highlights
Sigma receptors were discovered in 1976 and initially classified as an additional class of opioid receptorse [1]
The σ1R has been recently characterized and cloned from guinea pig [9], human [10], mouse [11,12], and rat tissues [13]. It is present mainly in the endoplasmic reticulum membrane (ER), the mitochondria associated ER membrane (MAM) and the plasma membrane [14]. σ1R consists of two transmembrane domains with both the amino and carboxy termini on the cytoplasmic side, whereas the loop between the transmembrane domains is located within the endoplasmic reticulum [15]. σ1R has been shown to act as a unique ligand-regulated molecular chaperone that modulates the activity of several proteins, such as the N-methyl-D-aspartate (NMDA) receptor[16] and several ion channels [17]
In a previously published paper we reported a series of 1,4-benzodioxane-based piperazines and piperidines as novel σR ligands with a good affinity for both receptor subtypes but lacking in adequate selectivity among sigma subtypes and sigma /5-HT1A receptors (Chart 1, 1a,b) [39]
Summary
ACCEPTED MANUSCRIPT Scouting New Sigma Receptor Ligands: Synthesis, Pharmacological Evaluation and Molecular Modeling of 1,3-Dioxolane-Based Structures and Derivatives. Silvia Franchini a, Umberto Maria Battisti a, Adolfo Prandi a, Annalisa Tait a, Chiara Borsari a, Elena Cichero b, Paola Fossa b, Antonio Cilia c, Orazio Prezzavento d, Simone Ronsisvalle d, Giuseppina Aricò e, Carmela Parenti e, Livio Brasili a,* a Dipartimento di Scienze della Vita, Università di Modena e Reggio Emilia, Via Campi 103, 41125 Modena, Italy. B Dipartimento di Farmacia, Scuola di Scienze Mediche e Farmaceutiche, Università di Genova, Viale Benedetto XV n.3, 16132. C Divisione Ricerca e Sviluppo, Recordati S.p.A., Via Civitali 1, 20148 Milano, Italy d Dipartimento di Scienze del Farmaco, Sezione di Chimica Farmaceutica, Università di Catania, Viale A. Doria 6, 95125 Catania, Italy e Dipartimento di Scienze del Farmaco, Sezione di Farmacologia e Tossicologia, Università di Catania, Viale A.
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