Blockade by psychotropic drugs of the muscarinic acetylcholine receptor in cultured nerve cells

The ability of antimuscarinics, tricyclic antidepressants, and antipsychotics to block the muscarinic acetylcholine receptor was determined using an assay for this receptor in cultured nerve cells. The technique involved the assay of receptor-mediated formation of guanosine 3',5'-cyclic phosphate (cyclic GMP) from radioactively labeled guanosine 5'-triphosphate in living mouse neuroblastoma cells (clone N1E-115). This cyclic GMP formation occurred rapidly (peak at 30 sec) and was dependent on the concentration of agonist. The psychotropic drugs tested blocked the muscarinic receptor and equilibrium dissociation constants (K(B)) were calculated from the parallel displacement of dose-response curves. The most potent compound was the antimuscarinic dexetimide (K(B)=5x10-¹¹M); while the least potent was the antipsychotic prochlorperazine (K(B)=4x10-⁵M). All tricyclic antidepressants with tertiary amine side chains were more potent (2-20 times) than those with secondary amine side chains; whereas phenothiazine potency correlated with the side chain structure as follows: piperadine >alkylamine ≥piperazine. These data for psychotherapeutic drugs may have direct clinical application.