{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T17:15:01Z","timestamp":1787764501036,"version":"build-2784847793"},"reference-count":77,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2022,9,23]],"date-time":"2022-09-23T00:00:00Z","timestamp":1663891200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000049","name":"National Institutes of Health\/National Institute on Aging","doi-asserted-by":"publisher","award":["R01AG068130"],"award-info":[{"award-number":["R01AG068130"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>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 (AUCplasma = 72.7 nmol\u00b7h\/mL) and an absolute oral bioavailability of 47.7%. Unfortunately, D-DOPA brain exposures were low with AUCbrain = 2.42 nmol\/g and AUCbrain\/plasma 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 &gt;200% enhancement in both plasma and brain exposures (AUCplasma = 185 nmol\u00b7h\/mL; AUCbrain = 5.48 nmol\u00b7h\/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.<\/jats:p>","DOI":"10.3390\/pharmaceutics14102018","type":"journal-article","created":{"date-parts":[[2022,9,23]],"date-time":"2022-09-23T04:07:07Z","timestamp":1663906027000},"page":"2018","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["D-DOPA Is a Potent, Orally Bioavailable, Allosteric Inhibitor of Glutamate Carboxypeptidase II"],"prefix":"10.3390","volume":"14","author":[{"given":"Sadakatali S.","family":"Gori","sequence":"first","affiliation":[{"name":"Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA"},{"name":"Johns Hopkins Drug Discovery, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ajit G.","family":"Thomas","sequence":"additional","affiliation":[{"name":"Johns Hopkins Drug Discovery, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arindom","family":"Pal","sequence":"additional","affiliation":[{"name":"Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA"},{"name":"Johns Hopkins Drug Discovery, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4537-0473","authenticated-orcid":false,"given":"Robyn","family":"Wiseman","sequence":"additional","affiliation":[{"name":"Johns Hopkins Drug Discovery, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA"},{"name":"Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5791-5939","authenticated-orcid":false,"given":"Dana V.","family":"Ferraris","sequence":"additional","affiliation":[{"name":"Johns Hopkins Drug Discovery, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Run-duo","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA"},{"name":"Johns Hopkins Drug Discovery, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Wu","sequence":"additional","affiliation":[{"name":"Johns Hopkins Drug Discovery, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jesse","family":"Alt","sequence":"additional","affiliation":[{"name":"Johns Hopkins Drug Discovery, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0216-7520","authenticated-orcid":false,"given":"Takashi","family":"Tsukamoto","sequence":"additional","affiliation":[{"name":"Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA"},{"name":"Johns Hopkins Drug Discovery, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA"},{"name":"Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9814-4157","authenticated-orcid":false,"given":"Barbara S.","family":"Slusher","sequence":"additional","affiliation":[{"name":"Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA"},{"name":"Johns Hopkins Drug Discovery, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA"},{"name":"Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA"},{"name":"Departments of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA"},{"name":"Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA"},{"name":"Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA"},{"name":"Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4059-2453","authenticated-orcid":false,"given":"Rana","family":"Rais","sequence":"additional","affiliation":[{"name":"Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA"},{"name":"Johns Hopkins Drug Discovery, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA"},{"name":"Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,9,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/S0167-4781(98)00200-0","article-title":"Mapping, genomic organization and promoter analysis of the human prostate-specific membrane antigen gene","volume":"1443","author":"Su","year":"1998","journal-title":"Biochim. 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