Comparative pharmacology of nicotine and ABT-418, a new nicotinic agonist.
ABT-418, a novel cholinergic ligand, was reported to possess potent cognitive-enhancing and anxiolytic properties in animal models with reduced side effects (Decker et al. 1994; Garvey et al. 1994) suggesting selectivity of effects. In this study, the binding properties of ABT-418 to [3H]-nicotine sites were evaluated and its pharmacology investigated in different tests in laboratory animals. ABT-418 binds with high affinity to 3H-nicotine binding sites in the brain with, however, a Ki (6 nM) less than that of nicotine (four-fold). In addition, it acts as a full nicotinic agonist in producing hypomotility, hypothermia and antinociception in mice and engendering nicotine-like responding in rat drug discrimination. The potency of ABT-418 is three to four times less than that of nicotine in all of the animal models, except for hypothermia. In addition, its behavioral effects are completely blocked by mecamylamine, a non-competitive nicotinic antagonist. Although activation of nicotinic receptors by ABT-418 produced several behavioral and pharmacological effects, our results do not suggest high selectivity of different effects as reported by Decker et al. (1994) and Garvey et al. (1994). However, it should be noted that we did not perform some of these tests that produced effects at low doses (Decker et al. 1994) and additional pharmacological studies are needed to establish its selectivity at multiple nicotinic receptors.
Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298-0613, USA.
M I
MI
Damaj
K R
KR
Creasy
S P
SP
Welch
J A
JA
Rosecrans
M D
MD
Aceto
B R
BR
Martin
D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D001667:Binding, Competitive; D004192:Discrimination, Psychological; D004305:Dose-Response Relationship, Drug; D007555:Isoxazoles / Q000494:pharmacology*; D008124:Locomotion / Q000187:drug effects*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009538:Nicotine / Q000494:pharmacology*; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D014151:Anti-Anxiety Agents; D007555:Isoxazoles; D011759:Pyrrolidines; C088383:3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole; D009538:Nicotine