Sigma receptors (σR) have proved to be an attractive pharmacological target for the treatment of several pathologies. In particular, σ1 ligands have been considered to play an important role in the treatment of various neurological disorders, including depression, schizophrenia, neuropathic pain, Alzheimer's and Parkinson’s disease. Moreover, it has been found that σR are involved in the modulation of cellular proliferation and cell death and σ1 antagonists and σ2 agonists may represent useful tools as anticancer and tumor imaging agents. Recently, we reported that a properly substituted 1,3-dioxolane moiety could be employed as suitable scaffold for developing ligands for both σ1R and σ2R.1 In this work we explore a new set of structural related analogues obtained by combining different substituted spiro-heterocyclic rings with appropriate σR pharmacophoric amines. Radioligand binding assay, performed on guinea pig brain membranes, identified BS148 (1-(1,4-ditiaspiro[4.5]decan-2-ylmethyl)-4-benzylpiperidne) as the most interesting compound of the series, displaying good affinity and selectivity for σ2R .The ability of BS148 to modulate the analgesic effect of the  agonist morphine was evaluated in-vivo by radiant heat tail-flick test. It exhibited anti-opioid effects on  receptor-mediated analgesia, suggesting an agonistic behavior at σ1R. Moreover, BS148 demonstrated to affect the growth (MTT test) of SK-MEL-28 and SK-MEL-2 melanoma cell lines in comparison to siramesine, suggesting an agonistic behavior at σ2R. The present work represents a new starting point for the design of potential therapeutically useful agents.

Discovery Of New Sigma-2 Receptor Agonist Endowed With Antiproliferative Activity / Franchini, Silvia; Sorbi, Claudia; Tait, Annalisa; Benassi, Luisa; Azzoni, Paola; Vaschieri, Crisitina; Pellacani, Giovanni; Prezzavento, Orazio; Ronsisvalle, Simine; Aricò, Giuseppina; Brasili, Livio. - (2016). (Intervento presentato al convegno XXIV National Meeting in Medicinal Chemistry tenutosi a Perugia, Italy nel 11-14 September 2016).

Discovery Of New Sigma-2 Receptor Agonist Endowed With Antiproliferative Activity

FRANCHINI, Silvia;SORBI, Claudia;TAIT, Annalisa;BENASSI, Luisa;AZZONI, Paola;PELLACANI, Giovanni;BRASILI, Livio
2016

Abstract

Sigma receptors (σR) have proved to be an attractive pharmacological target for the treatment of several pathologies. In particular, σ1 ligands have been considered to play an important role in the treatment of various neurological disorders, including depression, schizophrenia, neuropathic pain, Alzheimer's and Parkinson’s disease. Moreover, it has been found that σR are involved in the modulation of cellular proliferation and cell death and σ1 antagonists and σ2 agonists may represent useful tools as anticancer and tumor imaging agents. Recently, we reported that a properly substituted 1,3-dioxolane moiety could be employed as suitable scaffold for developing ligands for both σ1R and σ2R.1 In this work we explore a new set of structural related analogues obtained by combining different substituted spiro-heterocyclic rings with appropriate σR pharmacophoric amines. Radioligand binding assay, performed on guinea pig brain membranes, identified BS148 (1-(1,4-ditiaspiro[4.5]decan-2-ylmethyl)-4-benzylpiperidne) as the most interesting compound of the series, displaying good affinity and selectivity for σ2R .The ability of BS148 to modulate the analgesic effect of the  agonist morphine was evaluated in-vivo by radiant heat tail-flick test. It exhibited anti-opioid effects on  receptor-mediated analgesia, suggesting an agonistic behavior at σ1R. Moreover, BS148 demonstrated to affect the growth (MTT test) of SK-MEL-28 and SK-MEL-2 melanoma cell lines in comparison to siramesine, suggesting an agonistic behavior at σ2R. The present work represents a new starting point for the design of potential therapeutically useful agents.
2016
XXIV National Meeting in Medicinal Chemistry
Perugia, Italy
11-14 September 2016
Franchini, Silvia; Sorbi, Claudia; Tait, Annalisa; Benassi, Luisa; Azzoni, Paola; Vaschieri, Crisitina; Pellacani, Giovanni; Prezzavento, Orazio; Ronsisvalle, Simine; Aricò, Giuseppina; Brasili, Livio
Discovery Of New Sigma-2 Receptor Agonist Endowed With Antiproliferative Activity / Franchini, Silvia; Sorbi, Claudia; Tait, Annalisa; Benassi, Luisa; Azzoni, Paola; Vaschieri, Crisitina; Pellacani, Giovanni; Prezzavento, Orazio; Ronsisvalle, Simine; Aricò, Giuseppina; Brasili, Livio. - (2016). (Intervento presentato al convegno XXIV National Meeting in Medicinal Chemistry tenutosi a Perugia, Italy nel 11-14 September 2016).
File in questo prodotto:
Non ci sono file associati a questo prodotto.
Pubblicazioni consigliate

Licenza Creative Commons
I metadati presenti in IRIS UNIMORE sono rilasciati con licenza Creative Commons CC0 1.0 Universal, mentre i file delle pubblicazioni sono rilasciati con licenza Attribuzione 4.0 Internazionale (CC BY 4.0), salvo diversa indicazione.
In caso di violazione di copyright, contattare Supporto Iris

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11380/1141480
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus ND
  • ???jsp.display-item.citation.isi??? ND
social impact