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

Haenisch, Britta; Hiemke, Christoph; Bönisch, Heinz

doi:10.1007/s00213-011-2281-9

Cited by 10 publications

(5 citation statements)

References 31 publications

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“…Urapidil is an agonist of the 5-HT 1A receptor and an antagonist of the α1-adrenoceptor [ 32 ]. Ipsapirone is a 5HT 1A partial agonist [ 33 , 34 ], while trimipramine displays modest inhibition of the serotonin reuptake transporter [ 35 ], as well as antagonistic activity at the 5HT 2A receptor, among others [ 36 ]. Additionally, we identified bromocriptine which targets a wide range of receptors, acting as an agonist at multiple dopamine and serotonin receptors, including the dopamine D 2 receptor and 5HT 1A , as well as an α-adrenergic receptor antagonist.…”

Section: Discussionmentioning

confidence: 99%

An in vivo drug repurposing screen and transcriptional analyses reveals the serotonin pathway and GSK3 as major therapeutic targets for NGLY1 deficiency

et al. 2022

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NGLY1 deficiency, a rare disease with no effective treatment, is caused by autosomal recessive, loss-of-function mutations in the N-glycanase 1 (NGLY1) gene and is characterized by global developmental delay, hypotonia, alacrima, and seizures. We used a Drosophila model of NGLY1 deficiency to conduct an in vivo, unbiased, small molecule, repurposing screen of FDA-approved drugs to identify therapeutic compounds. Seventeen molecules partially rescued lethality in a patient-specific NGLY1 deficiency model, including multiple serotonin and dopamine modulators. Exclusive dNGLY1 expression in serotonin and dopamine neurons, in an otherwise dNGLY1 deficient fly, was sufficient to partially rescue lethality. Further, genetic modifier and transcriptomic data supports the importance of serotonin signaling in NGLY1 deficiency. Connectivity Map analysis identified glycogen synthase kinase 3 (GSK3) inhibition as a potential therapeutic mechanism for NGLY1 deficiency, which we experimentally validated with TWS119, lithium, and GSK3 knockdown. Strikingly, GSK3 inhibitors and a serotonin modulator rescued size defects in dNGLY1 deficient larvae upon proteasome inhibition, suggesting that these compounds act through NRF1, a transcription factor that is regulated by NGLY1 and regulates proteasome expression. This study reveals the importance of the serotonin pathway in NGLY1 deficiency, and serotonin modulators or GSK3 inhibitors may be effective therapeutics for this rare disease.

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Section: Discussionmentioning

confidence: 99%

An in vivo drug repurposing screen and transcriptional analyses reveals the serotonin pathway and GSK3 as major therapeutic targets for NGLY1 deficiency

et al. 2022

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“…The steroidal antimineralocorticoid spironolactone, the synthetic hormone drospirenone, the alpha blocker tamsulosin, the angiotensin receptor antagonist telmisartan, and the muscarinic antagonist trospium chloride were also determined as potent inhibitors (> 85% inhibition) of OCT2-mediated metformin uptake. Indeed, doxepin, trimipramine, and trospium chloride were identified as potent OCT2-inhibitors before, however the respective studies did not use metformin but MPP + as the probe substrate [ 8 , 17 , 18 ]. We confirmed previous findings demonstrating that amitriptyline, lansoprazole, omeprazole, pantoprazole, sertraline and sitagliptin were potent inhibitors of OCT2-mediated metformin transport with IC 50 values in a low micromolar range [ 19 – 21 ].…”

Section: Discussionmentioning

confidence: 99%

Substrate-Dependent Inhibition of the Human Organic Cation Transporter OCT2: A Comparison of Metformin with Experimental Substrates

et al. 2015

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The importance of the organic cation transporter OCT2 in the renal excretion of cationic drugs raises the possibility of drug-drug interactions (DDIs) in which an inhibitor (perpetrator) drug decreases OCT2-dependent renal clearance of a victim (substrate) drug. In fact, there are clinically significant interactions for drugs that are known substrates of OCT2 such as metformin. To identify drugs as inhibitors for OCT2, individual drugs or entire drug libraries have been investigated in vitro by using experimental probe substrates such as 1-methyl-4-phenylpyridinium (MPP+) or 4–4-dimethylaminostyryl-N-methylpyridinium (ASP+). It has been questioned whether the inhibition data obtained with an experimental probe substrate such as MPP+ or ASP+ might be used to predict the inhibition against other, clinical relevant substrates such as metformin. Here we compared the OCT2 inhibition profile data for the substrates metformin, MPP+ and ASP+. We used human embryonic kidney (HEK 293) cells stably overexpressing human OCT2 as the test system to screen 125 frequently prescribed drugs as inhibitors of OCT2-mediated metformin and MPP+ uptake. Data on inhibition of OCT2-mediated ASP+ uptake were obtained from previous literature. A moderate correlation between the inhibition of OCT2-mediated MPP+, ASP+, and metformin uptake was observed (pairwise r s between 0.27 and 0.48, all P < 0.05). Of note, the correlation in the inhibition profile between structurally similar substrates such as MPP+ and ASP+ (Tanimoto similarity T = 0.28) was even lower (r s = 0.27) than the correlation between structurally distinct substrates, such as ASP+ and metformin (T = 0.01; r s = 0.48) or MPP+ and metformin (T = 0.01; r s = 0.40). We identified selective as well as universal OCT2 inhibitors, which inhibited transport by more than 50% of one substrate only or of all substrates, respectively. Our data suggest that the predictive value for drug-drug interactions using experimental substrates rather than the specific victim drug is limited.

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“…Urapidil is an agonist of the 5-HT 1A receptor and an antagonist of the α1-adrenoceptor (Buch, 2010). Ipsapirone is a 5HT 1A partial agonist (Lesch et al, 1990;Newman-Tancredi et al, 1998), while trimipramine displays modest inhibition of the serotonin reuptake transporter (Haenisch et al, 2011), as well as antagonistic activity at the 5HT 2A receptor, among others (Gross et al, 1991). Additionally, we identified bromocriptine which targets a wide range of receptors, acting as an agonist at multiple dopamine and serotonin receptors, including the dopamine D 2 receptor and 5HT 1A , as well as an α-adrenergic receptor antagonist.…”

Section: Discussionmentioning

confidence: 99%

An in vivo drug repurposing screen and transcriptional analyses reveals the serotonin pathway and GSK3 as major therapeutic targets for NGLY1 deficiency

Hope

Berman

Peterson

et al. 2021

Preprint

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NGLY1 deficiency, a rare disease with no effective treatment, is caused by autosomal recessive, loss-of-function mutations in the N-glycanase 1 (NGLY1) gene and is characterized by global developmental delay, hypotonia, alacrima, and seizures. We used an adult Drosophila model of NGLY1 deficiency to conduct an in vivo, unbiased, small molecule, repurposing screen of FDA-approved drugs to identify therapeutic compounds. Seventeen molecules rescued lethality in a patient-specific NGLY1 deficiency model, including multiple serotonin and dopamine modulators. Exclusive dNGLY1 expression in serotonin and dopamine neurons, in an otherwise dNGLY1-null fly, was sufficient to rescue lethality. Further, genetic modifier and transcriptomic data supports the importance of serotonin signaling in NGLY1 deficiency. Connectivity Map analysis identified glycogen synthase kinase 3 (GSK3) inhibition as a potential therapeutic mechanism for NGLY1 deficiency, which we experimentally validated with TWS119 and lithium. Strikingly, GSK3 inhibitors and a serotonin modulator rescued size defects in dNGLY1 deficient larvae upon proteasome inhibition, suggesting that these compounds act through NRF1, a transcription factor that regulates proteasome expression. This study reveals the importance of the serotonin pathway in NGLY1 deficiency, and serotonin modulators or GSK3 inhibitors may be effective therapeutics for this rare disease.

show abstract

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

Cited by 10 publications

References 31 publications

An in vivo drug repurposing screen and transcriptional analyses reveals the serotonin pathway and GSK3 as major therapeutic targets for NGLY1 deficiency

An in vivo drug repurposing screen and transcriptional analyses reveals the serotonin pathway and GSK3 as major therapeutic targets for NGLY1 deficiency

Substrate-Dependent Inhibition of the Human Organic Cation Transporter OCT2: A Comparison of Metformin with Experimental Substrates

An in vivo drug repurposing screen and transcriptional analyses reveals the serotonin pathway and GSK3 as major therapeutic targets for NGLY1 deficiency

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