Inhibitory potencies of trimipramine and its main metabolites at human monoamine and organic cation transporters

  title={Inhibitory potencies of trimipramine and its main metabolites at human monoamine and organic cation transporters},
  author={Britta Haenisch and Christoph Hiemke and Heinz Bönisch},
RationaleThe antidepressant trimipramine shows an atypical pharmacological profile and its mechanism of action is still obscure.ObjectivesThe present study investigated whether trimipramine and three of its metabolites interact with targets of other antidepressants, namely, the human monoamine transporters for noradrenaline (hNAT), serotonin (hSERT), and dopamine (hDAT), and with the human organic cation transporters (hOCT1, hOCT2, and hOCT3) which are expressed in the brain and are known to be… 
Interaction of antidepressant and antipsychotic drugs with the human organic cation transporters hOCT1, hOCT2 and hOCT3
Under the assumption of a tenfold accumulation in the brain, bupropion, nefazodone and clozapine may notably inhibit the corresponding hOCTs and it remains to be shown whether such a direct inhibition plays a role in the clinical effects of these three drugs.
Substrates and Inhibitors of Organic Cation Transporters (OCTs) and Plasma Membrane Monoamine Transporter (PMAT) and Therapeutic Implications.
  • H. Bönisch
  • Medicine
    Handbook of experimental pharmacology
  • 2021
All known drugs acting as substrates or inhibitors of these four organic cation transporters, independently of whether the transporter is expressed in the central nervous system (CNS) or in peripheral tissues are discussed.
Substrate-Dependent Inhibition of the Human Organic Cation Transporter OCT2: A Comparison of Metformin with Experimental Substrates
The data suggest that the predictive value for drug-drug interactions using experimental substrates rather than the specific victim drug is limited, and selective as well as universal OCT2 inhibitors are identified.
Active Metabolites as Antidepressant Drugs: The Role of Norquetiapine in the Mechanism of Action of Quetiapine in the Treatment of Mood Disorders
The available data are sufficient to arrive at the conclusion that antidepressant activity of quetiapine is mediated, at least in part, by the active metabolite norquetiAPine, which selectively inhibits noradrenaline reuptake, is a partial 5-HT1A receptor agonist, and acts as an antagonist at presynaptic α2,5-HT2C, and 5- HT7 receptors.
Antidepressants and Circadian Rhythm: Exploring Their Bidirectional Interaction for the Treatment of Depression
It is expected that this review will promote the investigation of chronotherapy for the treatment of depression, contribute to a better understanding of the relationship between antidepressants and circadian rhythms, and consequently promote the development of new therapeutics.
An in vivo drug repurposing screen and transcriptional analyses reveals the serotonin pathway and GSK3 as major therapeutic targets for NGLY1 deficiency
The importance of the serotonin pathway in NGLY1 deficiency is revealed, and serotonin modulators or GSK3 inhibitors may be effective therapeutics for this rare disease.
Therapeutic drug monitoring for antidepressant drug treatment.
The aim of this review is to summarize the current status of TDM for antidepressant drugs and discuss the literature with regard to response optimization, pharmacovigilance and economic benefits and with regards to needs for further research.


Pharmacological profile of antidepressants and related compounds at human monoamine transporters.
Using radioligand binding assays, the equilibrium dissociation constants (KD's) for 37 antidepressants, three of their metabolites, some mood stabilizers, and assorted other compounds for the human serotonin, norepinephrine, and dopamine transporters are determined to help predict some possible adverse effects and drug-drug interactions of antidepressants and related compounds.
Trimipramine: Pharmacological reevaluation and comparison with clozapine
It was found that trimipramine did not alter the electrically-induced release of noradrenaline and 5-hydroxytryptamine from slices of the cerebral cortex of the rat, in concentrations of less than 1 microM.
Interference of the noradrenergic neurotoxin DSP4 with neuronal and nonneuronal monoamine transporters
DSP4’s high-affinity uptake through the NAT together with its completely irreversible mode of interaction with the NAT may contribute to its selectivity as noradrenergic neurotoxin.
Interaction of the human plasma membrane monoamine transporter (hPMAT) with antidepressants and antipsychotics
The PMAT which is highly expressed in the human brain may be involved in the modulation of central monoaminergic neurotransmission and it may be a target for drugs used to treat depression and schizophrenia, i.e., dysregulations of the monoamine homeostasis in the central nervous system (CNS).
Effect of trimipramine, an atypical tricyclic antidepressant, on the activities of various enzymes involved in the metabolism of biogenic amines
  • P. Yu, A. Boulton
  • Chemistry, Medicine
    Progress in Neuro-Psychopharmacology and Biological Psychiatry
  • 1990
Neither trimipramine nor amitriptyline, at concentrations up to 1 mM, exhibited any significant effect on phenylalanine hydroxylase, tyrosine hydrogenase, L-aromatic amino acid decarboxylase or tyosine aminotransferase, but Monoamine oxidase was inhibited by both drugs with the greatest effect being on MAO-B.
Uptake inhibition of biogenic amines by newer antidepressant drugs: Relevance to the dopamine hypothesis of depression
The dopamine theory of depression was studied by assessing the effect of antidepressant drugs on uptake of dopamine, noradrenaline, and serotonin in synaptosomes from rat brain, and five newer drugs showed rather potent inhibition of 3H-dopamine uptake in corpus striatum.
Identity of the Organic Cation Transporter OCT3 as the Extraneuronal Monoamine Transporter (uptake2) and Evidence for the Expression of the Transporter in the Brain*
The transport characteristics and steroid sensitivity provide strong evidence for the molecular identity of OCT3 as uptake2, and regional distribution studies with in situ hybridization show that OCT3 is expressed widely in different brain regions, especially in the hippocampus, cerebellum, and cerebral cortex.
Trimipramine, a tricyclic antidepressant exerting atypical actions on the central noradrenergic system.
The results demonstrate that the down-regulation of central noradrenergic sensitivity in the rat is not a prerequisite for clinical efficacy of antidepressants in man.
Antagonism by antidepressants of neurotransmitter receptors of normal human brain in vitro.
At the human brain histamines 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.
Metabolism of trimipramine in man.
  • H. Maurer
  • Chemistry, Medicine
  • 1989
3 overlapping metabolic pathways can be postulated: N-dealkylation of the nitrogen in the iminodibenzyl ring, 1- and 2-fold N-demethylation of analsis in the side chain and 1-and-2-fold aromatic hydroxylation at one of the hydroxy groups.