Pharmacological properties of the active metabolites of the antidepressants desipramine and citalopram

Abstract

Although major metabolites of some antidepressant drugs are know to be active, their pharmacological effects are poorly characterized. Two of the most selective antidepressants, desipramine (selectively inhibits norepinephrine reuptake) and citalopram (selectively inhibits serotonin reuptake) are frequently used in animal studies of antidepressant action, as well as being useful therapeutically. The primary aim of this study was to determine the affinity of desmethyldesipramine, an active metabolite of desipramine, for the rat norepinephrine and serotonin transporters, as well as for the rat α 2 -adrenoceptor. The pharmacological characteristics of desmethyldesipramine and desmethylcitalopram, an active metabolite of citalopram, were also determined for various human transporters and neurotransmitter receptors. Competition binding studies using [³H]nisoxetine and [³H]citalopram showed desipramine to be 25 times more selective for the rat norepinephrine as compared to serotonin transporter (6.2 nM vs. 158 nM) whereas desmethyldesipramine is 12 times more selective for the serotonin over the norepinephrine transporter (12.8 nM vs. 153 nM). Interestingly, the affinity of desmethyldesipramine for the serotonin transporter is similar to the affinity of desipramine for the norepinephrine transporter. Desipramine and desmethyldesipramine were found to have a lower affinity for the rat α 2A(D) -adrenoceptor than the transporters, suggesting that this receptor is not a major site of action for either compound. Thus, the pharmacological effects of desipramine in rats may be attributed not only to the inhibition of the norepinephrine transporter by desipramine but also to the inhibition of serotonin transporter by the active metabolite desmethyldesipramine.

The Antidepressant Desipramine Is an Arrestin-biased Ligand at the α2A-Adrenergic Receptor Driving Receptor Down-regulation in Vitro and in Vivo

“…1A), consistent with a previous report (10). Although the binding of DMI to NET occurs with a much higher affinity (nanomolar), a low micromolar value is nevertheless within the reported physiological therapeutic range of the drug (see Table 1).…”

In Vivo Characterization of a Series of 18F-Diaryl Sulfides (18F-2-(2′-((Dimethylamino)Methyl)-4′-(Fluoroalkoxy)Phenylthio)Benzenamine) for PET Imaging of the Serotonin Transporter

“…Nisoxetine, a NET-selective inhibitor, also appeared to have some inhibitory effect, but like escitalopram, it had no inhibitory effect in the cerebellum. Escitalopram and nisoxetine are known to be highly selective for SERT (100,000-fold over NET) and NET (1,000-fold over SERT), respectively (25,26). If the inhibition seen with nisoxetine pretreatment was attributable to a NET-binding component, then incomplete inhibition by escitalopram in those 4 regions would be expected.…”

Pharmacologically Active Drug Metabolites: Impact on Drug Discovery and Pharmacotherapy

“…67). The metabolites have lower affinity for the reuptake transporter than the parent (6-to 8-fold) (Owens et al, 1997;Deupree et al, 2007) and circulate at lower steadystate concentrations than the parent (Sidhu et al, 1997). Thus, the metabolites contribute very little to the antidepressant effect of citalopram.…”