RT Journal Article
SR Electronic
T1 Neurotransmitter Receptor and Transporter Binding Profile of Antidepressants and Their Metabolites
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 1305
OP 1322
VO 283
IS 3
A1 Michael J. Owens
A1 W. Neal Morgan
A1 Susan J. Plott
A1 Charles B. Nemeroff
YR 1997
UL http://jpet.aspetjournals.org/content/283/3/1305.abstract
AB 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 (Ki) of 13 antidepressants and 6 metabolites for the rat and human SERT and NET. TheKi values for eight of the antidepressants and three metabolites were also determined for the rat 5-HT1A, 5-HT2A 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-HT1A, 5-HT2A, 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. The American Society for Pharmacology and Experimental Therapeutics