New Synthesis of Tic-Hydantoins Sigma-1 Ligands and Pharmacological Evaluation on Cocaine-Induced Stimulant Effects

M.      Toussaint; M.-A.      Debreu-Fontaine; T.      Maurice; P.      Melnyk

Abstract

Activation of the newly identified σ1 chaperone protein is involved in several aspects of the psychostimulant and addictive effects of cocaine. The development of ligands that selectively target the σ1 protein may lead to putative potent anti-cocaine agents. We report here a new and more convergent synthetic pathway to amino side chain substituted hydantoins. Twenty new analogs of our lead compound were synthesized. None of them showed better in vitro affinity for σ1 receptor than our lead compound. Nevertheless, three of them, obtained as racemates, showed high in vitro affinity and selectivity for σ1 receptor. A preliminary in vivo evaluation of their pharmacological activity identified compound 22 as one that increases cocaine-induced locomotor stimulation and therefore acts as a potential efficient σ1 agonist.

Keywords: 1 protein, agonist, hydantoin, isoquinoline, cocaine, addiction, racemates, protein, hyperlocomotion, stereotypies, Tic-hydantoin, stereochemistry, Glennon's model, HOBt, HBTU, Thin layer chromatography, HPLC, TLC, flash chromatography, Whatman GF/B filters, ad libitum, Dunnett's post-hoc comparison test