Remacemide hydrochloride and ARL 15896AR lack abuse potential: additional differences from other uncompetitive NMDA antagonists.
This study was designed to determine the possible abuse liability and phencyclidine-like effects of the low-affinity uncompetitive N-methyl-D-aspartate (NMDA) antagonists remacemide hydrochloride [(+/-)-2-amino-N-(1-methyl-1,2-diphenylethyl)-acetamine hydrochloride] and ARL 15896AR [(+)-alpha-phenyl-2-pyridine-ethanamine dihydrochloride]. For the abuse-liability studies, in rats trained to self-administer cocaine intravenously (0.1 mg/kg/injection), doses of remacemide HCl, ARL 15896AR, phencyclidine, and saline were made available, and the number of injections self-administered was recorded. In different sets of rats, we assessed the ability of these drugs to induce phencyclidine-like stereotyped behavior. Doses of the compounds were expressed as multiples of the 50% effective dose (ED50), as determined from the maximal electroshock (MES) test by using either oral or intravenous administration. None of the remacemide hydrochloride or ARL 15896AR doses was self-administered at a level higher than that of the saline vehicle, unlike cocaine and phencyclidine, which were self-administered at high and moderate levels, respectively. Unlike that with remacemide hydrochloride and ARL 15896AR, oral administration of the high-affinity uncompetitive NMDA receptor-antagonists phencyclidine, ARL 16247 [N-(3-ethylphenyl)-N-methyl-N'-naphthylguanidine] and MK-801 engendered phencyclidine-like stereotypy at doses near their MES ED50 values. These data confirm the unusual safety of remacemide hydrochloride and ARL 15896AR and demonstrate that they do not possess reinforcing properties. As such, they are unlikely to present a drug-abuse problem in human beings.
Hudzik
T J
TJ
Division of Biology, Astra Arcus USA, Rochester, NY 14602, USA.
Freedman
L
L
Palmer
G C
GC
D000081:Acetamides / Q000009:adverse effects*; D000284:Administration, Oral; D000818:Animals; D000927:Anticonvulsants / Q000009:adverse effects*; D001522:Behavior, Animal / Q000187:drug effects; D003042:Cocaine / Q000008:administration & dosage; D003216:Conditioning, Operant; D004305:Dose-Response Relationship, Drug; D004597:Electroshock; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D010622:Phencyclidine / Q000008:administration & dosage / Q000494:pharmacology; D011725:Pyridines; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D012055:Reinforcement Schedule; D012640:Seizures / Q000517:prevention & control; D012646:Self Administration; D013239:Stereotyped Behavior / Q000187:drug effects; D019966:Substance-Related Disorders / Q000453:epidemiology / Q000209:etiology*
D000081:Acetamides; D000927:Anticonvulsants; D011725:Pyridines; D016194:Receptors, N-Methyl-D-Aspartate; C096406:alpha-phenyl-2-pyridineethanamine dihydrochloride; C067553:remacemide; D003042:Cocaine; D010622:Phencyclidine