New bifunctional antioxidant/σ1 agonist ligands: Preliminary chemico-physical and biological evaluation.
We previously reported bifunctional sigma-1 (σ1) ligands endowed with antioxidant activity (1 and 2). 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 compounds 1 and 2. In vivo evaluation of compounds 1, 2, (R)-1, 7, and 12 showed σ1 agonist pharmacological profile. Chemico-physical studies revealed that amides 2, 11 and 12 were more stable than corresponding esters 1, 6 and 7 under our experimental conditions. Antioxidant properties were exhibited by fluoro derivatives 7 and 12 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 compounds 7 and 12 could be promising tools to investigate the disorders in which σ1 receptor dysfunction and oxidative stress are contemporarily involved.
Department of Drug Sciences, Medicinal Chemistry Section, University of Catania, Viale A. Doria 6, 95125 Catania, Italy.
Emanuela
E
Arena
Department of Pharmacy, University G. d'Annunzio, Via dei Vestini 31, 66100 Chieti, Italy.
Ivana
I
Cacciatore
Department of Pharmacy, University G. d'Annunzio, Via dei Vestini 31, 66100 Chieti, Italy.
Laura S
LS
Cerasa
Department of Pharmacy, University G. d'Annunzio, Via dei Vestini 31, 66100 Chieti, Italy; Department of Molecular Biology and Genetics, Faculty of Science, Erzurum Technical University, Erzurum, Turkey.
Hasan
H
Turkez
Department of Drug Sciences, Medicinal Chemistry Section, University of Catania, Viale A. Doria 6, 95125 Catania, Italy.
Valeria
V
Pittalà
Department of Drug Sciences, Medicinal Chemistry Section, University of Catania, Viale A. Doria 6, 95125 Catania, Italy.
Lorella
L
Pasquinucci
Department of Drug Sciences, Medicinal Chemistry Section, University of Catania, Viale A. Doria 6, 95125 Catania, Italy.
Agostino
A
Marrazzo
Department of Drug Sciences, Pharmacology Section, University of Catania, Viale A. Doria 6, 95125 Catania, Italy.
Carmela
C
Parenti
Department of Pharmacy, University G. d'Annunzio, Via dei Vestini 31, 66100 Chieti, Italy.
Antonio
A
Di Stefano
Department of Drug Sciences, Medicinal Chemistry Section, University of Catania, Viale A. Doria 6, 95125 Catania, Italy. Electronic address: prezzave@unict.it.
Orazio
O
Prezzavento
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D066241:Carbon-13 Magnetic Resonance Spectroscopy; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D008024:Ligands; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D066244:Proton Magnetic Resonance Spectroscopy; D051381:Rats; D017207:Rats, Sprague-Dawley; D017480:Receptors, sigma / Q000037:antagonists & inhibitors*; D013056:Spectrophotometry, Ultraviolet; D000097605:Sigma-1 Receptor
D000975:Antioxidants; D008024:Ligands; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor
Antioxidants; Chemical and enzymatic stabilities; Lipoic acid; Neuroprotection; Oxidative stress; σ(1) receptors