Pharmacological properties of the active metabolites of the antidepressants desipramine and citalopram
Introduction
Two of the main classes of drugs used to treat major depressive disorder in adults are the tricyclic antidepressants and the selective serotonin reuptake inhibitors. Many of the tricyclic antidepressants or their metabolites are selective norepinephrine reuptake inhibitors including desipramine which has a 400-fold higher affinity for the norepinephrine transporter than the serotonin transporter in humans (Owens et al., 1997). By contrast, escitalopram is a selective serotonin reuptake inhibitor which has a 7000-fold selectivity for the serotonin transporter over the norepinephrine transporter (Owens et al., 2001). Although both of these drugs are metabolized to compounds that are pharmacologically active, very little is known about the affinities of the metabolites for the norepinephrine transporter and serotonin transporter or various neurotransmitter receptors.
In the rat, the major metabolite of desipramine is desmethyldesipramine. Chronic treatment of rats with desmethyldesipramine has been shown to down-regulate the β-adrenoceptor with a potency similar to desipramine (Argenti and D'Mello, 1994, Deupree et al., 2007). Treatment of rats with desipramine can result in the concentration of desmethyldesipramine reaching levels similar to that of the parent compound (Kozisek et al., 2007). Thus, desmethyldesipramine may well contribute significantly to the antidepressant effect of desipramine. However, no studies have reported its affinity for either norepinephrine transporter or serotonin transporter. Escitalopram is metabolized to desmethylcitalopram and didesmethylcitalopram. Desmethylcitalopram has a similar affinity for the human serotonin transport as citalopram and a 500-fold lower affinity for norepinephrine transporter (Tatsumi et al., 1997), but little else is known about its pharmacological characteristics.
The primary focus of this study was to ascertain whether the some pharmacological effects of desmethyldesipramine could be attributed to binding to norepinephrine transporter and/or serotonin transporter. Our findings indicate that desmethyldesipramine has a higher affinity for serotonin transporter than norepinephrine transporter suggesting that part of the pharmacological effects of administered desipramine could be due to inhibition of both norepinephrine transporter and serotonin transporter in rats. In addition, we report the pharmacology profile of desmethyldesipramine and desmethylcitalopram for various human transporters and neurotransmitter receptors. The affinity of desmethyldesipramine for the α2-adrenoceptor was also determined in order to rule out the possibility that some of the pharmacological effects of this metabolite are due to an interaction with this receptor.
Section snippets
Materials
Desmethyldesipramine and desmethylcitalopram were provided by the National Institute of Mental Health's Chemical Synthesis and Drug Supply Program. Imipramine and desipramine were purchased from Sigma-Aldrich (St. Louis, MO, USA). [3H]Nisoxetine (86 Ci/mmol) was obtained from Perkin Elmer Life Sciences (Boston, MA, USA). [3H]Citalopram (84 Ci/mmol) and [3H]RX821002 (50 Ci/mmol) were purchased from Amersham Biosciences (Piscataway, NJ, USA). Adult male Sprague–Dawley rat brains were obtained
Affinity of desipramine and desmethyldesipramine for rat norepinephrine transporter and serotonin transporter
The affinity of desipramine and its metabolite, desmethyldesipramine, was determined for both norepinephrine transporter and serotonin transporter in rat brain homogenates. For comparison purposes the affinity of escitalopram for these transporters was also determined, because escitalopram is one of the most selective of the selective serotonin reuptake inhibitors. [3H]Nisoxetine bound to both a high affinity and a low affinity binding site in rat brain homogenates. The data from five
Transporter affinities
The major finding of this study is that desmethyldesipramine has a 12-fold higher affinity for serotonin transporter than norepinephrine transporter, and that its affinity for serotonin transporter is similar to the affinity of desipramine for norepinephrine transporter. Thus, the inhibition of serotonin transporter by the metabolite desmethyldesipramine may contribute significantly to the pharmacological effects of desipramine in rats.
In rats the major metabolite of desipramine is
Acknowledgements
This research was supported by Grant R01 MH064772 from the National Institute of Mental Health of the National Institutes of Health. Human receptor profiling and Ki data were generously provided by the National Institute of Mental Health's Psychoactive Drug Screening Program (NIMH PDSP). The NIMH PDSP is directed by Bryan L. Roth MD, PhD at the University of North Carolina at Chapel Hill and Project Officer Jamie Driscol at NIMH, Bethesda MD, USA. Contract # NO1MH32004.
References (28)
- et al.
Affinities of venlafaxine and various reuptake inhibitors for the serotonin and norepinephrine transporters
Eur. J. Pharmacol.
(1998) - et al.
Atomoxetine increases extracellular levels of norepinephrine and dopamine in prefrontal cortex of rat: a potential mechanism for efficacy in attention deficit/hyperactivity disorder
Neuropsychopharmacology
(2002) - et al.
[3H]nisoxetine—a radioligand for noradrenaline reuptake sites: correlation with inhibition of [3H]noradrenaline uptake and effect of DSP-4 lesioning and antidepressant treatments
Neuropharmacology
(1996) - et al.
Appropriate dosing regimens for treating juvenile rats with desipramine for neuropharmacological and behavioral studies
J. Neurosci. Methods
(2007) - et al.
Second-generation SSRIs: human monoamine transporter binding profile of escitalopram and R-fluoxetine
Biol. Psychiatry
(2001) - et al.
Tyrosine residue 271 of the norepinephrine transporter is an important determinant of its pharmacology
Brain Res. Mol. Brain Res.
(2001) - et al.
Inhibition of the norepinephrine transporter by the venom peptide chi-MrIA. Site of action, Na+ dependence, and structure–activity relationship
J. Biol. Chem.
(2003) - et al.
Molecular cloning and expression of a 5-hydroxytryptamine7 serotonin receptor subtype
J. Biol. Chem..
(1993) - et al.
Antagonism of the five cloned human muscarinic cholinergic receptors expressed in CHO-K1 cells by antidepressants and antihistaminics
Biochem. Pharmacol.
(1993) - et al.
Pharmacological profile of antidepressants and related compounds at human monoamine transporters
Eur. J. Pharmacol.
(1997)
The pharmacodynamics of desipramine and desmethyldesipramine in rats
J. Pharmacol. Exp. Ther.
Blockade of presynaptic alpha-receptors and of amine uptake in the rat brain by the antidepressant mianserine
Naunyn Schmiedebergs Arch. Pharmacol.
Influence of phenobarbital on the distribution and elimination of desmethylimipramine in the rat
Biochem. Pharmacol.
Relationship between the inhibition constant (KI) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reaction
Biochem. Pharmacol.
Cited by (24)
In vivo studies of effects of antidepressants on parotid salivary secretion in the rat
2016, Archives of Oral BiologyCitation Excerpt :Furthermore, the escitalopram metabolite desmethylcitalopram displays lower human SERT to human NET selectivity ratio (Tatsumi, Groshan, Blakely, & Richelson, 1997), which thus is a plausible candidate for explaining the findings. Also, supplementary binding studies of desmethylcitalopram show low affinity towards muscarinic receptors and α-adrenoceptors (Deupree, Montgomery, & Bylund, 2007). Citalopram N-demethylation results in a less lipophilic metabolite, less effective in permeating the blood brain barrier, which in turn should lead to higher metabolite concentrations in the periphery.
α<inf>2</inf> adrenergic receptor trafficking as a therapeutic target in antidepressant drug action
2015, Progress in Molecular Biology and Translational SciencePharmacology of cognitive enhancers for exposure-based therapy of fear, anxiety and trauma-related disorders
2015, Pharmacology and TherapeuticsCitation Excerpt :Despite their common effect of serotonin transporter inhibition, SSRIs are known to differ with regard to their pharmacological properties. Along these lines, some SSRIs (e.g. paroxetine) show additional noradrenaline transporter-inhibiting properties via their metabolites (Owens et al., 1997), while others (e.g. citalopram) show continued selectivity for the serotonergic system (Deupree et al., 2007). In this respect, differential effect sizes of SSRIs are to be expected.
Pharmacokinetics
2014, Biochemical PharmacologyCitation Excerpt :The process of compound metabolism is, on occasion, a double-edged sword as it does not always lead to compound inactivation and detoxification. Some compounds may be converted to pharmacologically active metabolites, e.g., the metabolites of tricyclic antidepressants [98] and imatinib [99], and/or to toxic metabolites, such as the metabolites of carbamazepine [100], methotrexate [101] and acetaminophen [102]. In these instances, understanding the PK of the relevant metabolite(s) is important for characterizing pharmacological effects and drug safety and for assessing risk.
The antidepressant desipramine is an arrestin-biased ligand at the α<inf>2A</inf>-adrenergic receptor driving receptor down-regulation in vitro and in vivo
2011, Journal of Biological ChemistryCitation Excerpt :The resulting pellet containing the crude synaptosomal fraction was then subjected to saturation radioligand binding as described above, with the addition of 1 μm prazosin to the reaction to block α2B- and α2CAR subtypes. Although previous studies have reported the binding of DMI to α2ARs (6, 8–10), the pharmacological nature of this interaction has not been fully investigated. We began by performing competition radioligand binding analysis in membrane preparations from HEK 293 cells to characterize the binding of DMI and the endogenous ligand NE (for comparison) to the α2AAR subtype specifically using a radioligand concentration of 4 nm (Fig. 1A).
DMI-induced sexual effects in male rats: Analysis of DMI's acute and chronic actions on copulatory behavior and on the genital motor pattern of ejaculation
2010, Pharmacology Biochemistry and Behavior