Neurotransmitter Receptor and Transporter Binding Profile of Antidepressants and Their Metabolites1

Abstract

Several new antidepressants that inhibit the serotonin (SERT) and norepinephrine transporters (NET) have been introduced into clinical practice the past several years. This report focuses on the further pharmacologic characterization of nefazodone and its metabolites within the serotonergic and noradrenergic systems, in comparison with other antidepressants. By use of radioligand binding assays, we measured the affinity (K_i) of 13 antidepressants and 6 metabolites for the rat and human SERT and NET. TheK_i values for eight of the antidepressants and three metabolites were also determined for the rat 5-HT_1A, 5-HT_2A and muscarinic cholinergic receptors, the guinea pig histamine₁ receptor and the humanalpha-1 and alpha-2 receptors. These data are useful for predicting side effect profiles and the potential for pharmacodynamic drug-drug interactions of antidepressants. Of particular interest were the findings that paroxetine, generally thought of as a selective SERT antagonist, possesses moderately high affinity for the NET and that venlafaxine, which has been described as a “dual uptake inhibitor”, possesses weak affinity for the NET. We observed significant correlations in SERT (r = 0.965) or NET (r = 0.983) affinity between rat and human transporters. Significant correlations were also observed between muscarinic cholinergic and NET affinity. There are several significant correlations between affinities for the 5-HT_1A, 5-HT_2A, histamine₁, alpha-1 andalpha-2 receptors. These novel findings, not widely described previously, suggest that many of the individual drugs studied in these experiments possess some structural characteristic that determines affinity for several G protein-coupled, but not muscarinic, receptors.