Two allosteric modulators interact at a common site on cardiac muscarinic receptors.
The abilities of gallamine, obidoxime, tetrahydroaminoacridine (THA), and 8-(N,N-diethylamino)octyl-3,4,5-trimethoxybenzoate (TMB-8) to alter the rate of dissociation of N-[3H]methylscopolamine from rat cardiac muscarinic receptors were investigated. All four ligands monotonically slowed the dissociation, with the order of potency gallamine > TMB-8 > THA > obidoxime. There was a dramatic difference in the efficacy of these allosteric modulators. Gallamine, TMB-8, and THA slowed the dissociation of N-methylscopolamine by > 90% at maximally effective concentrations, whereas obidoxime was capable of slowing it by only about 50%. In a manner analogous to the action of a partial agonist, obidoxime was able to partially reverse the effects of the other three modulators. Furthermore, the concentration-dependent effects of combinations of obidoxime and gallamine were in good agreement with the model of competitive interaction between these two ligands. These results provide the first evidence that two muscarinic allosteric modulators interact competitively at a well defined site.
Ellis
J
J
Department of Psychiatry, University of Vermont, Burlington 05405.
Seidenberg
M
M
D000494:Allosteric Regulation; D000818:Animals; D001665:Binding Sites; D005703:Gallamine Triethiodide / Q000494:pharmacology; D005707:Gallic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D066298:In Vitro Techniques; D009206:Myocardium / Q000378:metabolism*; D009768:Obidoxime Chloride / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011976:Receptors, Muscarinic / Q000378:metabolism*; D013619:Tacrine / Q000494:pharmacology
D011976:Receptors, Muscarinic; D009768:Obidoxime Chloride; D013619:Tacrine; C006014:8-(N,N-diethylamino)octyl-3,4,5-trimethoxybenzoate; D005707:Gallic Acid; D005703:Gallamine Triethiodide