Discovery and characterization of potent small molecule inhibitors of the high affinity proline transporter |
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Authors: | Xuan-Chuan Yu Wandong Zhang Arian Oldham Eric Buxton Shiv Patel Nguyen Nghi David Tran Thomas H. Lanthorn Catherine Bomont Zhi-Cai Shi Qingyun Liu |
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Affiliation: | 1. Department of Pharmaceutical Discovery, Lexicon Pharmaceuticals Inc., 8800 Technology Forest Place, The Woodlands, TX 77381, United States;2. Department of Neurology, Lexicon Pharmaceuticals Inc., 8800 Technology Forest Place, The Woodlands, TX 77381, United States;3. Department of Medicinal Chemistry, Lexicon Pharmaceuticals Inc., 350 Carter Road, Princeton, NJ 08540, United States |
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Abstract: | The mammalian proline transporter (PROT) is a high affinity Na+/Cl−-dependent transporter expressed in specific regions of the brain. It is homologous to other neurotransmitter transporters such as glycine, norepinephrine, serotonin, and dopamine transporters. PROT is enriched in glutamatergic synaptic terminals and may play an important role in the regulation of excitatory neurotransmission. No non-peptide small molecule inhibitors have been described for this transporter. To study its physiological role in the central nervous system and evaluate its potential as a therapeutic target, we established cell lines that stably express recombinant hPROT and characterized its kinetic properties for proline uptake. We then screened for inhibitors and identified a series of compounds that inhibit hPROT-mediated proline uptake. A known compound, benztropine, was found to inhibit hPROT with an IC50 of 0.75 μM. A series of novel compounds were also found, one of which, LP-403812, showed an IC50 of approximately 0.1 μM on both recombinant human and mouse PROT without significant inhibition of glycine and dopamine transporters at concentrations up to 10 μM. This compound also inhibited proline transporter activity of mouse brain synaptosomes with the same potency. These inhibitors provide important tools for the understanding of PROT functions in the brain and may lead to the development of therapeutic agents for certain neurological disorders. |
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Keywords: | PROT, proline transporter hPROT, human proline transporter mPROT, mouse proline transporter DAT, dopamine transporter GLYT, glycine transporter GGFL, des tyrosyl leu-enkephalin |
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