New bifunctional antioxidant/sigma(1) agonist ligands: Preliminary chemico-physical and biological evaluation

Arena E., Cacciatore I., Cerasa L. S., Turkez H., Pittala V., Pasquinucci L., ...Daha Fazla

BIOORGANIC & MEDICINAL CHEMISTRY, cilt.24, sa.14, ss.3149-3156, 2016 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 24 Sayı: 14
  • Basım Tarihi: 2016
  • Doi Numarası: 10.1016/j.bmc.2016.05.045
  • Dergi Adı: BIOORGANIC & MEDICINAL CHEMISTRY
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus
  • Sayfa Sayıları: ss.3149-3156
  • Anahtar Kelimeler: sigma(1) receptors, Oxidative stress, Neuroprotection, Chemical and enzymatic stabilities, Antioxidants, Lipoic acid, SELECTIVE CHOLINERGIC LESION, SIGMA-1 RECEPTOR, OXIDATIVE STRESS, KAPPA-B, RATS, BINDING, ACID, INVOLVEMENT, SUPPRESSION, MODULATION
  • Atatürk Üniversitesi Adresli: Hayır

Özet

We previously reported bifunctional sigma-1 (sigma(1)) 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. sigma(1) and sigma(2) affinities, antioxidant properties, and chemico-physical profiles were evaluated. Para derivatives, while maintaining strong sigma(1) affinity, displayed improved sigma(1) selectivity compared to the parent compounds 1 and 2. In vivo evaluation of compounds 1, 2, (R)-1, 7, and 12 showed sigma(1) 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 sigma(1) 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 sigma(1) receptor dysfunction and oxidative stress are contemporarily involved. (C) 2016 Elsevier Ltd. All rights reserved.