New bifunctional antioxidant/σ1 agonist ligands: Preliminary chemico-physical and biological evaluation. Issue 14 (15th July 2016)

• Record Type: Journal Article
• Authors: Arena, Emanuela; Cacciatore, Ivana; Cerasa, Laura S.; Turkez, Hasan; Pittalà, Valeria; Pasquinucci, Lorella; Marrazzo, Agostino; Parenti, Carmela; Di Stefano, Antonio; Prezzavento, Orazio
• Is Part Of: Bioorganic & medicinal chemistry. Volume 24:Issue 14(2016)
• Page Start: 3149
• Page End: 3156
• Publication Date: 2016-07-15
• Subjects: σ1 receptors -- Oxidative stress -- Neuroprotection -- Chemical and enzymatic stabilities -- Antioxidants -- Lipoic acid; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2016.05.045
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: We previously reported bifunctional sigma-1 (σ1 ) ligands endowed with antioxidant activity (1 and2 ). In the present paper, pure enantiomers ( R )-1 and ( R )-2 along with the corresponding p -methoxy (6, 11 ), p -fluoro derivatives (7, 12 ) were synthesized. σ1 and σ2 affinities, antioxidant properties, and chemico-physical profiles were evaluated. Para derivatives, while maintaining strong σ1 affinity, displayed improved σ1 selectivity compared to the parent compounds1 and2 . In vivo evaluation of compounds1, 2, ( R )-1, 7, and12 showed σ1 agonist pharmacological profile. Chemico-physical studies revealed that amides2, 11 and12 were more stable than corresponding esters1, 6 and7 under our experimental conditions. Antioxidant properties were exhibited by fluoro derivatives7 and12 being able to increase total antioxidant capacity (TAC). Our results underline that p -substituents have an important role on σ1 selectivity, TAC, chemical and enzymatic stabilities. In particular, our data suggest that new very selective compounds7 and12 could be promising tools to investigate the disorders in which σ1 receptor dysfunction and oxidative stress are contemporarily involved.