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Eur J Med Chem. 2016 Apr 13;112:1-19. doi: 10.1016/j.ejmech.2016.01.059. Epub 2016 Feb 1.

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

Author information

1
Dipartimento di Scienze della Vita, Università di Modena e Reggio Emilia, Via Campi 103, 41125 Modena, Italy.
2
Dipartimento di Farmacia, Scuola di Scienze Mediche e Farmaceutiche, Università di Genova, Viale Benedetto XV n.3, 16132 Genova, Italy.
3
Divisione Ricerca e Sviluppo, Recordati S.p.A., Via Civitali 1, 20148 Milano, Italy.
4
Dipartimento di Scienze del Farmaco, Sezione di Chimica Farmaceutica, Università di Catania, Viale A. Doria 6, 95125 Catania, Italy.
5
Dipartimento di Scienze del Farmaco, Sezione di Farmacologia e Tossicologia, Università di Catania, Viale A. Doria 6, 95125 Catania, Italy.
6
Dipartimento di Scienze della Vita, Università di Modena e Reggio Emilia, Via Campi 103, 41125 Modena, Italy. Electronic address: livio.brasili@unimore.it.

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.

KEYWORDS:

1,3-Dioxolane; Piperazine; Piperidine; Receptor-mediated analgesia; Sigma receptors ligands; Sigma-1; Sigma-2

PMID:
26874044
DOI:
10.1016/j.ejmech.2016.01.059
[Indexed for MEDLINE]

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