Antagonism by antidepressants of neurotransmitter receptors of normal human brain in vitro

Using radioligand binding techniques, we determined the equilibrium dissociation constants (K(D)S) for a series of antidepressants at the histamine H₁, muscarinic acetylcholine, alpha-1 and alpha-2 adrenergic and dopamine (D-2) receptors of normal human brain tissue obtained at autopsy. Twenty-five different antidepressants were studied at all but the D-2 receptor at which the number was 13 (including a metabolite of an antidepressant). Of all the receptor interactions studied, that at the histamine H₁ receptor was in general the most potent interaction of this class of compounds, corresponding to results from studies using animal tissue as the source of receptors. At the human brain histamine H₁ receptor, antidepressants remained among the most potent histamine H₁ antagonists known, although their affinities for human receptors were lower than those for animal receptors. The most potent and the least potent compounds at the receptors were doxepin (K(D) = 0.24 nM) and fluvoxamine (K(D) = 109 μM) at the histamine H₁ receptor, amitriptyline (K(D) = 18 nM) and trazodone (K(D) = 324 μM) at the muscarinic receptor, doxepin (K(D) = 24 nM) and viloxazine (K(D) = 14 μM) at the alpha-1 receptor, mianserin (K(D) = 73 nM) and bupropion (K(D) = 81 μM) at the alpha-2 receptor and amoxapine (K(D) = 160 nM) and trazodone (K(D) = 3800 nM) at the D-2 receptor, respectively. In general, compared to older drugs, the newer compounds tended to have lower affinities for these receptors.