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.