title: Analgesic and toxic effects of ABT-594 resemble epibatidine and nicotine in rats.
abstract: The present study directly compared the antinociceptive and toxic effects of the neuronal nicotinic receptor agonist ABT-594 ((R)-5-(2-azetidinylmethoxy)-2-chloropyridine) with (-)-nicotine and (+)-epibatidine. Like (-)-nicotine (0.8 and 1.6 mg/kg s.c.) and (+)-epibatidine (0.005 and 0.01 mg/kg s.c.), ABT-594 (0.05 and 0.1 mg/kg s.c.) increased response latencies in the hot-plate test in rats, indicating that it has antinociceptive activity. In contrast to (-)-nicotine and (+)-epibatidine, ABT-594 did not cause rotarod impairment at antinociceptive doses but did cause hypothermia and life-threatening adverse effects including seizures. ABT-594 (0.01 and 0.1 mg/kg i.v.) also produced a dose-dependent increase in blood pressure resembling that observed with (-)-nicotine (0.03, 0.1 and 0. 03 mg/kg i.v.) and (+)-epibatidine (0.001 and 0.003 mg/kg i.v.). Both the antinociceptive and toxic effects (convulsions and hypertension) were abolished by pretreatment with the brain penetrant neuronal nAChR antagonist mecamylamine (1 mg/kg s.c.; i.v. for cardiovascular studies), demonstrating that these actions of ABT-594 were mediated via activation of neuronal nicotinic receptors. Continuous infusion of ABT-594 (0.2 mg/kg per day s.c.) to rats for 7 days followed by challenge with mecamylamine (1 mg/kg i.p.) induced a nicotine-like abstinence syndrome suggesting that ABT-594 has nicotine-like dependence liability. These findings indicate that the acute safety profile of ABT-594 is not significantly improved over other nicotinic analgesics.
authors.affiliation: Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, UK.
authors.forename: S
authors.initials: S
authors.lastname: Boyce
authors.forename: J K
authors.initials: JK
authors.lastname: Webb
authors.forename: S L
authors.initials: SL
authors.lastname: Shepheard
authors.forename: M G N
authors.initials: MGN
authors.lastname: Russell
authors.forename: R G
authors.initials: RG
authors.lastname: Hill
authors.forename: N M J
authors.initials: NMJ
authors.lastname: Rupniak
mesh_terms: D018712:Analgesics, Non-Narcotic / Q000037:antagonists & inhibitors / Q000494:pharmacology* / Q000633:toxicity*; D000818:Animals; D001384:Azetidines / Q000037:antagonists & inhibitors / Q000494:pharmacology* / Q000633:toxicity; D001522:Behavior, Animal / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000037:antagonists & inhibitors / Q000494:pharmacology* / Q000633:toxicity*; D006358:Hot Temperature; D006973:Hypertension / Q000139:chemically induced; D008297:Male; D008464:Mecamylamine / Q000494:pharmacology; D009538:Nicotine / Q000037:antagonists & inhibitors / Q000494:pharmacology* / Q000633:toxicity*; D018722:Nicotinic Agonists / Q000494:pharmacology* / Q000633:toxicity*; D018733:Nicotinic Antagonists / Q000494:pharmacology; D010147:Pain Measurement / Q000187:drug effects; D004856:Postural Balance / Q000187:drug effects; D011725:Pyridines / Q000037:antagonists & inhibitors / Q000494:pharmacology* / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects; D012640:Seizures / Q000139:chemically induced / Q000517:prevention & control; D019966:Substance-Related Disorders / Q000523:psychology
chemical_list: C109763:5-(2-azetidinylmethoxy)-2-chloropyridine; D018712:Analgesics, Non-Narcotic; D001384:Azetidines; D019086:Bridged Bicyclo Compounds, Heterocyclic; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D011725:Pyridines; D008464:Mecamylamine; D009538:Nicotine; C082748:epibatidine