title: Antinociceptive and toxic effects of (+)-epibatidine oxalate attributable to nicotinic agonist activity.
abstract: 1. Epibatidine is an analgesic substance, isolated from the skin of the poisonous frog Epipedobates tricolor, for which the mechanism of action was previously unknown. 2. The IC50 of synthetic (+)-epibatidine oxalate (the naturally occurring isomer) for [3H]-nicotine binding to rat whole-brain membranes was 0.1 nM. The (-)-isomer also exhibited high affinity (IC50 = 0.2 nM). 3. (+)- and (-)-Epibatidine exhibited much lower affinity for displacement of the muscarinic ligand [3H]-N-methylscopolamine binding to rat cortical membranes (Kapp = 6.9 microM and 16.0 microM respectively). The (+)-enantiomer of epibatidine had an antagonist/agonist (NMS/oxo-M) binding ratio of 4.2 This is consistent with a muscarinic antagonist profile. 4. (+)-Epibatidine oxalate (10 microM) did not cause significant (> 30%) displacement of radioligand binding to opioid, excitatory amino acid, benzodiazepine, 5-HT, dopamine, adrenaline or peptide receptors. 5. (+)- and (-)-Epibatidine (5-20 micrograms kg-1 s.c.) doubled response latency in the mouse hot-plate test. Antinociception and behavioural depression induced by (+)-epibatidine (5 micrograms kg-1) was fully blocked by the nicotinic antagonists mecamylamine (2 mg kg-1 s.c.) or dihydro-beta-erythroidine (2 mg kg-1 s.c.). The muscarinic antagonist scopolamine (0.4 and 10 mg kg-1 s.c.) caused partial reversal of antinociception induced by (+)-epibatidine in mice, but not in rats. 6. These findings demonstrate that (+)-epibatidine oxalate salt is a highly selective and potent nicotinic analgesic agent.
authors.affiliation: Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex.
authors.forename: N M
authors.initials: NM
authors.lastname: Rupniak
authors.forename: S
authors.initials: S
authors.lastname: Patel
authors.forename: R
authors.initials: R
authors.lastname: Marwood
authors.forename: J
authors.initials: J
authors.lastname: Webb
authors.forename: J R
authors.initials: JR
authors.lastname: Traynor
authors.forename: J
authors.initials: J
authors.lastname: Elliott
authors.forename: S B
authors.initials: SB
authors.lastname: Freedman
authors.forename: S R
authors.initials: SR
authors.lastname: Fletcher
authors.forename: R G
authors.initials: RG
authors.lastname: Hill
mesh_terms: D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects; D001643:Bridged Bicyclo Compounds / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D019086:Bridged Bicyclo Compounds, Heterocyclic; D006168:Guinea Pigs; D006930:Hyperalgesia / Q000139:chemically induced; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D018727:Muscarinic Antagonists; D009292:Narcotic Antagonists; D018722:Nicotinic Agonists / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D018733:Nicotinic Antagonists; D010147:Pain Measurement / Q000187:drug effects; D011725:Pyridines / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011976:Receptors, Muscarinic / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000378:metabolism; D011957:Receptors, Opioid / Q000378:metabolism; D013237:Stereoisomerism
chemical_list: D000700:Analgesics; D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D018727:Muscarinic Antagonists; D009292:Narcotic Antagonists; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D011725:Pyridines; D011976:Receptors, Muscarinic; D011978:Receptors, Nicotinic; D011957:Receptors, Opioid; C082748:epibatidine