D-DOPA Is a Potent, Orally Bioavailable, Allosteric Inhibitor of Glutamate Carboxypeptidase II
Glutamate carboxypeptidase-II (GCPII) is a zinc-dependent metalloenzyme implicated in numerous neurological disorders. The pharmacophoric requirements of active-site GCPII inhibitors makes them highly charged, manifesting poor pharmacokinetic (PK) properties. Herein, we describe the discovery and ch...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-09-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/14/10/2018 |
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| author | Sadakatali S. Gori Ajit G. Thomas Arindom Pal Robyn Wiseman Dana V. Ferraris Run-duo Gao Ying Wu Jesse Alt Takashi Tsukamoto Barbara S. Slusher Rana Rais |
| author_facet | Sadakatali S. Gori Ajit G. Thomas Arindom Pal Robyn Wiseman Dana V. Ferraris Run-duo Gao Ying Wu Jesse Alt Takashi Tsukamoto Barbara S. Slusher Rana Rais |
| author_sort | Sadakatali S. Gori |
| collection | DOAJ |
| description | Glutamate carboxypeptidase-II (GCPII) is a zinc-dependent metalloenzyme implicated in numerous neurological disorders. The pharmacophoric requirements of active-site GCPII inhibitors makes them highly charged, manifesting poor pharmacokinetic (PK) properties. Herein, we describe the discovery and characterization of catechol-based inhibitors including L-DOPA, D-DOPA, and caffeic acid, with sub-micromolar potencies. Of these, D-DOPA emerged as the most promising compound, with good metabolic stability, and excellent PK properties. Orally administered D-DOPA yielded high plasma exposures (AUC<sub>plasma</sub> = 72.7 nmol·h/mL) and an absolute oral bioavailability of 47.7%. Unfortunately, D-DOPA brain exposures were low with AUC<sub>brain</sub> = 2.42 nmol/g and AUC<sub>brain</sub><sub>/plasma</sub> ratio of 0.03. Given reports of isomeric inversion of D-DOPA to L-DOPA via D-amino acid oxidase (DAAO), we evaluated D-DOPA PK in combination with the DAAO inhibitor sodium benzoate and observed a >200% enhancement in both plasma and brain exposures (AUC<sub>plasma</sub> = 185 nmol·h/mL; AUC<sub>brain</sub> = 5.48 nmol·h/g). Further, we demonstrated GCPII target engagement; orally administered D-DOPA with or without sodium benzoate caused significant inhibition of GCPII activity. Lastly, mode of inhibition studies revealed D-DOPA to be a noncompetitive, allosteric inhibitor of GCPII. To our knowledge, this is the first report of D-DOPA as a distinct scaffold for GCPII inhibition, laying the groundwork for future optimization to obtain clinically viable candidates. |
| first_indexed | 2024-03-09T19:35:44Z |
| format | Article |
| id | doaj.art-8dd66acf64054ef395a30b21fda30f08 |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-09T19:35:44Z |
| publishDate | 2022-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-8dd66acf64054ef395a30b21fda30f082023-11-24T01:53:57ZengMDPI AGPharmaceutics1999-49232022-09-011410201810.3390/pharmaceutics14102018D-DOPA Is a Potent, Orally Bioavailable, Allosteric Inhibitor of Glutamate Carboxypeptidase IISadakatali S. Gori0Ajit G. Thomas1Arindom Pal2Robyn Wiseman3Dana V. Ferraris4Run-duo Gao5Ying Wu6Jesse Alt7Takashi Tsukamoto8Barbara S. Slusher9Rana Rais10Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USAJohns Hopkins Drug Discovery, Johns Hopkins School of Medicine, Baltimore, MD 21205, USADepartment of Neurology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USAJohns Hopkins Drug Discovery, Johns Hopkins School of Medicine, Baltimore, MD 21205, USAJohns Hopkins Drug Discovery, Johns Hopkins School of Medicine, Baltimore, MD 21205, USADepartment of Neurology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USAJohns Hopkins Drug Discovery, Johns Hopkins School of Medicine, Baltimore, MD 21205, USAJohns Hopkins Drug Discovery, Johns Hopkins School of Medicine, Baltimore, MD 21205, USADepartment of Neurology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USADepartment of Neurology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USADepartment of Neurology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USAGlutamate carboxypeptidase-II (GCPII) is a zinc-dependent metalloenzyme implicated in numerous neurological disorders. The pharmacophoric requirements of active-site GCPII inhibitors makes them highly charged, manifesting poor pharmacokinetic (PK) properties. Herein, we describe the discovery and characterization of catechol-based inhibitors including L-DOPA, D-DOPA, and caffeic acid, with sub-micromolar potencies. Of these, D-DOPA emerged as the most promising compound, with good metabolic stability, and excellent PK properties. Orally administered D-DOPA yielded high plasma exposures (AUC<sub>plasma</sub> = 72.7 nmol·h/mL) and an absolute oral bioavailability of 47.7%. Unfortunately, D-DOPA brain exposures were low with AUC<sub>brain</sub> = 2.42 nmol/g and AUC<sub>brain</sub><sub>/plasma</sub> ratio of 0.03. Given reports of isomeric inversion of D-DOPA to L-DOPA via D-amino acid oxidase (DAAO), we evaluated D-DOPA PK in combination with the DAAO inhibitor sodium benzoate and observed a >200% enhancement in both plasma and brain exposures (AUC<sub>plasma</sub> = 185 nmol·h/mL; AUC<sub>brain</sub> = 5.48 nmol·h/g). Further, we demonstrated GCPII target engagement; orally administered D-DOPA with or without sodium benzoate caused significant inhibition of GCPII activity. Lastly, mode of inhibition studies revealed D-DOPA to be a noncompetitive, allosteric inhibitor of GCPII. To our knowledge, this is the first report of D-DOPA as a distinct scaffold for GCPII inhibition, laying the groundwork for future optimization to obtain clinically viable candidates.https://www.mdpi.com/1999-4923/14/10/2018catecholglutamate carboxypeptidase IICNSD-DOPApharmacokineticsbrain penetration |
| spellingShingle | Sadakatali S. Gori Ajit G. Thomas Arindom Pal Robyn Wiseman Dana V. Ferraris Run-duo Gao Ying Wu Jesse Alt Takashi Tsukamoto Barbara S. Slusher Rana Rais D-DOPA Is a Potent, Orally Bioavailable, Allosteric Inhibitor of Glutamate Carboxypeptidase II Pharmaceutics catechol glutamate carboxypeptidase II CNS D-DOPA pharmacokinetics brain penetration |
| title | D-DOPA Is a Potent, Orally Bioavailable, Allosteric Inhibitor of Glutamate Carboxypeptidase II |
| title_full | D-DOPA Is a Potent, Orally Bioavailable, Allosteric Inhibitor of Glutamate Carboxypeptidase II |
| title_fullStr | D-DOPA Is a Potent, Orally Bioavailable, Allosteric Inhibitor of Glutamate Carboxypeptidase II |
| title_full_unstemmed | D-DOPA Is a Potent, Orally Bioavailable, Allosteric Inhibitor of Glutamate Carboxypeptidase II |
| title_short | D-DOPA Is a Potent, Orally Bioavailable, Allosteric Inhibitor of Glutamate Carboxypeptidase II |
| title_sort | d dopa is a potent orally bioavailable allosteric inhibitor of glutamate carboxypeptidase ii |
| topic | catechol glutamate carboxypeptidase II CNS D-DOPA pharmacokinetics brain penetration |
| url | https://www.mdpi.com/1999-4923/14/10/2018 |
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