Neuroleptic binding to muscarinic M₂ receptors of normal human heart in vitro and comparison with binding to M₁ and dopamine D₂ receptors of brain

We determined by radioligand binding the equilibrium dissociation constants (K_d's) for seventeen neuroleptics at muscarinic M₂ receptors of human heart atrium and compared these data with our previous data for binding to muscarinic M₁ and dopamine D₂ receptors of human brain. At the M₂ receptor, the most potent compound was thioridazine; the least, molindone. If selectivity is defined as K_d at one receptor ≤ 0.1 K_d at the other receptor, no compound was selective for the M₂ subtype. Two compounds, clozapine and triflupromazine, were selective for the M₁ subtype. Thus, few neuroleptics have the assumed preferred property of M₁ over M₂ subtype selectivity. Such a feature could reduce extrapyramidal side effects, while reducing the likelihood of certain cardiac side effects.