New synthesis of tic-hydantoins sigma-1 ligands and pharmacological evaluation on cocaine-induced stimulant effects.
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.
Toussaint
M
M
CNRS UMR 8161 F-59021, Lille, France.
Debreu-Fontaine
M-A
MA
Maurice
T
T
Melnyk
P
P
D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D003042:Cocaine / Q000494:pharmacology*; D006801:Humans; D006827:Hydantoins / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D008024:Ligands; D009043:Motor Activity; D017480:Receptors, sigma / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000378:metabolism; D000097605:Sigma-1 Receptor
D000697:Central Nervous System Stimulants; D003042:Cocaine; D006827:Hydantoins; D008024:Ligands; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor