Pharmacological activity of N-methyl-carbamylcholine, a novel acetylcholine receptor agonist with selectivity for nicotinic receptors.
N-Methyl-carbamylcholine (also called N-methyl-carbachol) is an analogue of the mixed muscarinic-nicotinic acetylcholine receptor agonist, carbachol. Previous studies have provided evidence that radiolabelled N-methyl-carbachol can bind selectively to nicotinic acetylcholine receptors in rat brain. To determine whether N-methyl-carbachol acts as an agonist or an antagonist at nicotine and/or muscarinic receptor sites, the present study examined the pharmacological activity of this compound on some cholinergically innervated tissues. N-Methyl-carbachol, like carbachol, depolarized rat isolated sympathetic ganglia and these effects were inhibited by a nicotinic antagonist, d-tubocurarine, but not by a muscarinic antagonist, atropine. Exposure of rat sympathetic ganglia to N-methyl-carbachol blocked the compound action potential generated in ganglia by stimulation of the pre-ganglionic trunk; this effect of N-methyl-carbachol was likely due to desensitization of the nicotinic response. N-Methyl-carbochol, like carbachol, stimulated the release of [3H]noradrenaline from cultured adrenal medullary cells that had been pre-loaded with [3H]noradrenaline; these effects were largely inhibited by a nicotinic antagonist, mecamylamine, while atropine produced less blockade. N-Methyl-carbachol contracted the frog isolated rectus abdominis muscle and the effect was completely blocked by d-tubocurarine. By contrast, contracture of the rectus abdominis produced by carbachol was partially inhibited by either atropine or d-tubocurarine. N-Methyl-carbachol, like carbachol, contracted the rat isolated ileum and these effects were completely blocked by atropine; however, N-methyl-carbachol was about 42 times less potent than carbachol for this effect. Intravenous injection of N-methyl-carbachol, like nicotine, to the rat produced a transient decrease followed by a more sustained rise in blood pressure while carbachol produced only a sustained decrease in blood pressure. The effects of N-methyl-carbachol and nicotine on blood pressure were blocked by pretreatment of the animal with a nicotinic antagonist, hexamethonium. N-methyl-carbachol, like nicotine, stimulated the release of [3H]dopamine from rat striatal synaptosomes, pre-loaded with [3H]dopamine; release induced by either N-methyl-carbachol or nicotine was inhibited by mecamylamine but not by atropine. In rat cerebral cortical slices pre-loaded with [3H]inositol, carbachol, but not N-methyl-carbachol, stimulated the accumulation of [3H]inositol-1-phosphate, an effect blocked by atropine but not by mecamylamine.(ABSTRACT TRUNCATED AT 400 WORDS)
Boksa
P
P
Department of Psychiatry, McGill University, Verdun, Quebec, Canada.
Quik
M
M
Mitchell
J B
JB
Collier
B
B
O'Neil
W
W
Quirion
R
R
D000313:Adrenal Medulla / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D002217:Carbachol / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D002417:Cattle; D005728:Ganglia, Sympathetic / Q000187:drug effects; D066298:In Vitro Techniques; D007295:Inositol Phosphates / Q000378:metabolism; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009638:Norepinephrine / Q000378:metabolism; D010525:Peripheral Nerves / Q000187:drug effects; D011894:Rana pipiens; D051381:Rats; D011919:Rats, Inbred Strains; D011950:Receptors, Cholinergic / Q000502:physiology*; D011976:Receptors, Muscarinic / Q000187:drug effects; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000378:metabolism*; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism
D007295:Inositol Phosphates; D011950:Receptors, Cholinergic; D011976:Receptors, Muscarinic; D011978:Receptors, Nicotinic; C053765:N-methylcarbamylcholine; D002217:Carbachol; D009638:Norepinephrine