RT Journal Article
SR Electronic
T1 (+/-)-Epibatidine elicits a diversity of in vitro and in vivo effects mediated by nicotinic acetylcholine receptors.
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 624
OP 631
VO 271
IS 2
A1 J P Sullivan
A1 M W Decker
A1 J D Brioni
A1 D Donnelly-Roberts
A1 D J Anderson
A1 A W Bannon
A1 C H Kang
A1 P Adams
A1 M Piattoni-Kaplan
A1 M J Buckley
YR 1994
UL http://jpet.aspetjournals.org/content/271/2/624.abstract
AB (+/-)-Epibatidine, exo-2-(6-chloro-3-pyridyl)-7-azabicyclo-[2.2.1] heptane, is a novel, potent analgesic agent that acts through nicotinic acetylcholine receptor (nAChR) mechanisms. This study sought to establish whether (+/-)-epibatidine, like (-)-nicotine, also displays a wide diversity of behavioral responses that are known to be elicited by nAChR activation or whether it demonstrates subtype selectivity for its interactions with nAChRs.(+/-)-Epibatidine displaced [3H](-)-cytisine binding to the alpha 4 beta 2 nAChR subtype in rat brain membranes with high affinity (Ki, 43 pM). The compound was approximately 5000-fold less potent (Ki = 230nM) in the displacement of [125I] alpha-bungarotoxin binding from the alpha-bungarotoxin-sensitive nAChR subtype present in rat brain but was a potent inhibitor (Ki, 2.7 nM) of [125I] alpha-bungarotoxin binding to the nAChR subtype in Torpedo electroplax, which is similar to that present in the neuromuscular junction. Functionally, (+/-)-epibatidine enhanced 86Rb+ flux in IMR 32 cells with an EC50 value of 7 nM. It was some 3000-fold more potent than (-)-nicotine (EC50 value, 21,000 nM) and was approximately 150-fold more potent (EC50 value, 0.4 nM) than (-)-nicotine (EC50 value = 60 nM) in increasing [3H]dopamine release from rat striatal slices. Remarkably, (+/-)-epibatidine was 40% to 50% more efficacious than (-)-nicotine in both functional assays. Both functional effects were blocked by the nAChR channel blocker, mecamylamine (100 microM). (+/-)-Epibatidine was 300 to 1000 times more potent than (-)-nicotine in the reduction of body temperature and locomotor activity in mice.(ABSTRACT TRUNCATED AT 250 WORDS)