Document Detail

Analgesic and toxic effects of ABT-594 resemble epibatidine and nicotine in rats.
MedLine Citation:
PMID:  10781917     Owner:  NLM     Status:  MEDLINE    
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.
S Boyce; J K Webb; S L Shepheard; M G Russell; R G Hill; N M Rupniak
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Publication Detail:
Type:  Comparative Study; Journal Article    
Journal Detail:
Title:  Pain     Volume:  85     ISSN:  0304-3959     ISO Abbreviation:  Pain     Publication Date:  2000 Apr 
Date Detail:
Created Date:  2000-06-21     Completed Date:  2000-06-21     Revised Date:  2008-11-21    
Medline Journal Info:
Nlm Unique ID:  7508686     Medline TA:  Pain     Country:  NETHERLANDS    
Other Details:
Languages:  eng     Pagination:  443-50     Citation Subset:  IM    
Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, UK.
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MeSH Terms
Analgesics, Non-Narcotic / antagonists & inhibitors,  pharmacology*,  toxicity*
Azetidines / antagonists & inhibitors,  pharmacology*,  toxicity
Behavior, Animal / drug effects
Bicyclo Compounds, Heterocyclic / antagonists & inhibitors,  pharmacology*,  toxicity*
Body Temperature / drug effects
Hot Temperature
Hypertension / chemically induced
Mecamylamine / pharmacology
Nicotine / antagonists & inhibitors,  pharmacology*,  toxicity*
Nicotinic Agonists / pharmacology*,  toxicity*
Nicotinic Antagonists / pharmacology
Pain Measurement / drug effects
Postural Balance / drug effects
Pyridines / antagonists & inhibitors,  pharmacology*,  toxicity*
Rats, Sprague-Dawley
Reaction Time / drug effects
Seizures / chemically induced,  prevention & control
Substance-Related Disorders / psychology
Reg. No./Substance:
0/5-(2-azetidinylmethoxy)-2-chloropyridine; 0/Analgesics, Non-Narcotic; 0/Azetidines; 0/Bicyclo Compounds, Heterocyclic; 0/Nicotinic Agonists; 0/Nicotinic Antagonists; 0/Pyridines; 140111-52-0/epibatidine; 54-11-5/Nicotine; 60-40-2/Mecamylamine

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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