ArticleBritish journal of pharmacology2015
Pharmacophore-based discovery of inhibitors of a novel drug/proton antiporter in human brain endothelial hCMEC/D3 cell line.
Article in British journal of pharmacology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 46 citations in OpenAlex.
- Comparative analysis of the uptake of the HFluids and barriers of the CNS · 2025Article
- An extended substrate spectrum of the proton organic cation antiporter and relation to other cation transporters.Basic & clinical pharmacology & toxicology · 2024Article
- The putative proton-coupled organic cation antiporter is involved in uptake of triptans into human brain capillary endothelial cells.Fluids and barriers of the CNS · 2024Article
- Proteomics-Based Transporter Identification by the PICK Method: Involvement of TM7SF3 and LHFPL6 in Proton-Coupled Organic Cation Antiport at the Blood-Brain Barrier.Pharmaceutics · 2022Article
- Discovery of novel SARS-CoV-2 inhibitors targeting the main protease MAntiviral research · 2022Article
- Substrates of the Human Brain Proton-Organic Cation Antiporter and Comparison with Organic Cation Transporter 1 Activities.International journal of molecular sciences · 2022Article
- Pharmacophore-Based Discovery of Substrates of a Novel Drug/Proton-Antiporter in the Human Brain Endothelial hCMEC/D3 Cell Line.Pharmaceutics · 2022Article
- Substrate-DependentInternational journal of molecular sciences · 2021Article
- Increased penetration of diphenhydramine in brain via proton-coupled organic cation antiporter in rats with lipopolysaccharide-induced inflammation.Brain, behavior, & immunity - health · 2021Article
- Carrier-mediated uptake of clonidine in cultured human lung cells.Naunyn-Schmiedeberg's archives of pharmacology · 2018Article
- Opioids and the Blood-Brain Barrier: A Dynamic Interaction with Consequences on Drug Disposition in Brain.Current neuropharmacology · 2017Review
- Imperatorin is Transported through Blood-Brain Barrier by Carrier-Mediated Transporters.Biomolecules & therapeutics · 2017Article
- Diphenhydramine as a selective probe to study HJournal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism · 2017Article
- A Rational Approach for the Identification of Non-Hydroxamate HDAC6-Selective Inhibitors.Scientific reports · 2016Article
- Blood-brain and retinal barriers show dissimilar ABC transporter impacts and concealed effect of P-glycoprotein on a novel verapamil influx carrier.British journal of pharmacology · 2016Article
- Pharmacophore-based discovery of inhibitors of a novel drug/proton antiporter in human brain endothelial hCMEC/D3 cell line.British journal of pharmacology · 2015Article
- A polyspecific drug/proton antiporter mediates diphenhydramine and clonidine transport at the mouse blood-retinal barrier.British journal of pharmacology · 2015Article
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Authors and funding
9 authors at 7 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
background and purposeAn influx drug/proton antiporter of unknown structure has been functionally demonstrated at the blood-brain barrier. This transporter, which handles some psychoactive drugs like diphenhydramine, clonidine, oxycodone, nicotine and cocaine, could represent a new pharmacological target in drug addiction therapy. However, at present there are no known drugs/inhibitors that effectively inhibit/modulate this transporter in vivo. EXPERIMENTAL APPROACH: The FLAPpharm approach was used to establish a pharmacophore model for inhibitors of this transporter. The inhibitory potency of 44 selected compounds was determined against the specific substrate, [(3)H]-clonidine, in the human cerebral endothelial cell line hCMEC/D3 and ranked as good, medium, weak or non-inhibitor. KEY
resultsThe pharmacophore model obtained was used as a template to screen xenobiotic and endogenous compounds from databases [Specs, Recon2, Human Metabolome Database (HMDB), human intestinal transporter database], and hypothetical candidates were tested in vitro to determine their inhibitory capacity with [(3)H]-clonidine. According to the transporter database, 80% of the proton antiporter inhibitor candidates could inhibit P-glycoprotein/MDR1/ABCB1 and specificity is improved by reducing inhibitor size/shape and increasing water solubility. Virtual screening results using HMDB and Recon2 for endogenous compounds appropriately scored tryptamine as an inhibitor. CONCLUSIONS AND IMPLICATIONS: The pharmacophore model for the proton-antiporter inhibitors was a good predictor of known inhibitors and allowed us to identify new good inhibitors. This model marks a new step towards the discovery of this drug/proton antiporter and will be of great use for the discovery and design of potent inhibitors that could potentially help to assess and validate its pharmacological role in drug addiction in vivo.
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