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

• Published in: European journal of medicinal chemistry Vol. 112; pp. 1 - 19
• Main Authors: Franchini, Silvia, Battisti, Umberto Maria, Prandi, Adolfo, Tait, Annalisa, Borsari, Chiara, Cichero, Elena, Fossa, Paola, Cilia, Antonio, Prezzavento, Orazio, Ronsisvalle, Simone, Aricò, Giuseppina, Parenti, Carmela, Brasili, Livio
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 13.04.2016; Elsevier
• Subjects: 1,3-Dioxolane; Analgesics, Opioid - chemistry; Analgesics, Opioid - pharmacology; Analgesics, Opioid - therapeutic use; Animals; Brain - drug effects; Brain - metabolism; Chemistry, Medicinal; Dioxolanes - chemistry; Dioxolanes - pharmacology; Dioxolanes - therapeutic use; Guinea Pigs; Humans; Life Sciences & Biomedicine; Ligands; Models, Molecular; Molecular Docking Simulation; Morphine - pharmacology; Morphine - therapeutic use; Pain - drug therapy; Pain - metabolism; Pharmacology & Pharmacy; Piperazine; Piperidine; Rats; Receptor-mediated analgesia; Receptors, Opioid, kappa - metabolism; Receptors, Opioid, mu - metabolism; Receptors, sigma - metabolism; Science & Technology; Sigma receptors ligands; Sigma-1; Sigma-2; Structure-Activity Relationship; Sigma receptors ligands; Piperazine; Receptor-mediated analgesia; Sigma-1; Sigma-2; Piperidine; 1,3-Dioxolane; PROTEIN; DOCKING; IDENTIFICATION; OPIOID RECEPTOR; CLONING; BIOLOGICAL EVALUATION; H-3 (+)-PENTAZOCINE; BINDING-SITES; BRAIN; HOMOLOGY MODEL
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2016.01.059

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. [Display omitted] •Twenty-six novel σR ligands bearing a variety of five-membered heterocyclic rings were synthesized.•Compound 25b exhibited the highest affinity and selectivity (pKi σ1 = 9.13, σ1/σ2 = 47).•25b showed anti-opioid effects on κ (KOP) and μ (MOP) receptor-mediated analgesia suggesting an agonistic behavior at σ1R.•Docking studies were performed on the theoretical σ1R homology model.