Antagonism by antidepressants of muscarinic acetylcholine receptors of human brain.
1 Twenty-two compounds classified as antidepressants, metabolites of antidepressants or putative antidepressants were assayed for their ability to antagonize the binding of (-)-[3H]-quinuclidinyl benzilate to muscarinic receptors in homogenates of human caudate nucleus. 2 Sixteen of these compounds were assayed for their ability to antagonize carbachol-stimulated cyclic guanosine 3',5'-monophosphate (cyclic GMP) synthesis by intact murine neuroblastoma cells (clone N1E-115). 3 Equilibrium dissociation constants (KDs) for these drugs and the muscarinic receptors of human brain spanned over 4 orders of magnitude, with the tertiary amine tricyclic antidepressant, amitriptyline (KD = 18 nM) being the most potent compound tested and trazodone (KD = 324 microM) the least potent. 4 There was a significant correlation between the data for human and murine receptors and for eight compounds (imipramine, desipramine, maprotiline, mianserin, 3-chloro-2-hydroxyimipramine, amoxapine, 2-hydroxyimipramine and iprindole). KD values measured by the two techniques were not significantly different.
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001921:Brain / Q000378:metabolism*; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000096:biosynthesis; D006801:Humans; D007700:Kinetics; D051379:Mice; D009374:Neoplasms, Experimental / Q000378:metabolism; D009447:Neuroblastoma / Q000378:metabolism; D010276:Parasympatholytics; D011950:Receptors, Cholinergic / Q000187:drug effects*; D011976:Receptors, Muscarinic / Q000187:drug effects*
D000928:Antidepressive Agents; D010276:Parasympatholytics; D011950:Receptors, Cholinergic; D011976:Receptors, Muscarinic; D006152:Cyclic GMP