Tic hydantoin sigma-1 agonist: pharmacological characterization on cocaine-induced stimulant and appetitive effects.
Activation of the newly identified sigma(1) chaperone protein is involved in several aspects of the psychostimulant and addictive effects of cocaine. The development of ligands that selectively target the sigma(1) protein may lead to putative potent anti-cocaine agents. Here, we synthetized substituted hydantoins with high affinity for the sigma(1) protein and evaluated their behavioral efficacy. Two pure enantiomers were designed and synthesized: tetrahydroisoquinoleine-hydantoin fused compounds 3 and 4. They increased cocaine-induced locomotor stimulation or sensitization. The most active enantiomer 4, facilitated CPP acquisition but failed to substitute for cocaine. When CPP was acquired with cocaine and then extinguished, 4 provoked reactivation of CPP. These observations showed that compound 4 shows a typical profile of sigma(1) protein activator, facilitating cocaine-induced behavioral effects. Preliminary ADME properties are in favour of an optimal therapeutic development. Such Tic-hydantoin compound may serve as a new effective agonist therapy in cocaine addiction.
Toussaint
Marion
M
CNRS UMR 8161, Team 3, Lille 2 University, Lille 1 University, Pasteur Institute of Lille, 59021 Lille, France.
Delair
Brice
B
Foulon
Catherine
C
Lempereur
Nadège
N
Vaccher
Claude
C
Maurice
Tangui
T
Melnyk
Patricia
P
D000704:Analysis of Variance; D000818:Animals; D001070:Appetitive Behavior / Q000187:drug effects*; D001522:Behavior, Animal / Q000187:drug effects; D002483:Cellulose, Oxidized / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D003042:Cocaine / Q000494:pharmacology*; D003216:Conditioning, Operant / Q000187:drug effects; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005029:Ethylenediamines / Q000494:pharmacology; D005108:Extinction, Psychological / Q000187:drug effects; D006827:Hydantoins / Q000737:chemistry / Q000494:pharmacology*; D006948:Hyperkinesis / Q000139:chemically induced*; D008124:Locomotion / Q000187:drug effects; D008297:Male; D051379:Mice; D011485:Protein Binding / Q000187:drug effects; D017480:Receptors, sigma / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000378:metabolism; D013997:Time Factors
D002483:Cellulose, Oxidized; D018765:Dopamine Uptake Inhibitors; D004791:Enzyme Inhibitors; D005029:Ethylenediamines; D006827:Hydantoins; C060002:INTERCEED; D017480:Receptors, sigma; C097963:N-(2-(3,4-Dichlorphenyl)ethyl)-N,N',N'-trimethyl-1,2-ethandiamin; D003042:Cocaine