Binding of semirigid nicotinic agonists to nicotinic and muscarinic receptors.
Isoarecolone methiodide (1-methyl-4-acetyl-1,2,3,6-tetrahydropyridine methiodide) was previously shown to be among the most potent agonists tested at the frog neuromuscular junction. Because nicotinic receptors from different sources vary in their selectivities, isoarecolone methiodide as well as 19 additional congeners, most of which were also previously tested at the frog neuromuscular junction, were studied in binding assays. Torpedo nobiliana was the tissue source for nicotinic receptors. Two types of experiments were conducted. The first evaluated the affinities of the agonists (including acetylcholine and carbamylcholine) for the recognition site by allowing the agonists to compete for that site with 125I-alpha-bungarotoxin. The inhibition potencies obtained correlated strongly (Spearman's correlation coefficient,-0.91) with the potency obtained at the frog neuromuscular junction. The second type of experiment evaluated the agonists for their ability to activate the receptor. The binding of [3H]perhydrohistrionicotoxin, which was employed as an indicator of the activation of the receptor, was measured in the presence of each of the agonists. Isoarecolone methiodide was the most potent of all. A few of the agonists (partial agonists) were incapable of fully enhancing this binding. For the full agonists, the concentration that produced half of the maximum binding of [3H]perhydrohistrionicotoxin was defined as the EC50. The correlation coefficient (Spearman's) for EC50 versus potency at the frog neuromuscular junction was -0.73, indicating innate differences between Torpedo and frog receptors. In addition, these compounds were tested for their affinity at muscarinic receptors from rat brain. Competition experiments were carried out using [3H]N-methylscopolamine. The affinity of isoarecolone methiodide was only about 7-fold lower than that of acetylcholine and less than 2-fold lower than that of carbamylcholine. In contrast, 1-methyl-4-acetylpiperazine methiodide was much more selective for nicotinic receptors. Its activity was similar to isoarecolone methiodide at the nicotinic receptor, but it was among the weakest compounds in its affinity for the muscarinic receptor.
Spivak
C E
CE
Addiction Research Center, National Institute on Drug Abuse, Baltimore, Maryland 21224.
Waters
J A
JA
Aronstam
R S
RS
D000818:Animals; D001115:Arecoline / Q000031:analogs & derivatives / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D008968:Molecular Conformation; D009469:Neuromuscular Junction / Q000187:drug effects; D010277:Parasympathomimetics / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D011976:Receptors, Muscarinic / Q000378:metabolism*; D011978:Receptors, Nicotinic / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014101:Torpedo
D010277:Parasympathomimetics; D011976:Receptors, Muscarinic; D011978:Receptors, Nicotinic; C053508:isoarecolone methiodide; D001115:Arecoline