Evidence map›Paper›PMID 36297453›Full record

ArticlePharmaceutics2022

D-DOPA Is a Potent, Orally Bioavailable, Allosteric Inhibitor of Glutamate Carboxypeptidase II.

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 and 1 more

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Pharmaceutics, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.

0numbers the graph read from it
0cells of the map it votes in
3citing papers in PubMed
0.4field-weighted citation impact, top 47% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

3 citing papers in PubMed, 4 citations in OpenAlex.

  1. Review
  2. Review
  3. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

11 authors at 1 institution in 1 country.

Sadakatali S GoriDepartment of Neurology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
Ajit G ThomasJohns Hopkins Drug Discovery, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
Arindom PalDepartment of Neurology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
Robyn WisemanJohns Hopkins Drug Discovery, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.ORCID 0000-0002-4537-0473
Dana V FerrarisJohns Hopkins Drug Discovery, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.ORCID 0000-0001-5791-5939
Run-Duo GaoDepartment of Neurology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
Ying WuJohns Hopkins Drug Discovery, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
Jesse AltJohns Hopkins Drug Discovery, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
Takashi TsukamotoDepartment of Neurology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.ORCID 0000-0002-0216-7520
Barbara S SlusherDepartment of Neurology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.ORCID 0000-0001-9814-4157
Rana RaisDepartment of Neurology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.ORCID 0000-0003-4059-2453
Johns Hopkins University · US

Funding

Development of GCPII inhibitors for the treatment of age-related cognitive disordersR01AG068130 · NIA · JOHNS HOPKINS UNIVERSITY · PI ARNSTEN, AMY F.T., SLUSHER, BARBARA STAUCH · 2020 to 2024
$3.8M
Pharmacology and Molecular Sciences Training Program: Enhancing Inclusivity Through Universal Design for Learning in Graduate CoursesT32GM135083 · NIGMS · JOHNS HOPKINS UNIVERSITY · PI Caren L. Freel Meyers · 2020 to 2026
$3.3M
NIA NIH HHS R01 AG068130NIA NIH HHS R01AG068130NIGMS NIH HHS T32 GM135083
6 · The paper itself

Abstract

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·h/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 >200% enhancement in both plasma and brain exposures (AUCplasma = 185 nmol·h/mL; AUCbrain = 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.

Indexed as

brain penetrationcatecholCNSD-DOPAglutamate carboxypeptidase IIpharmacokinetics

Identifiers

PMID36297453
PMCPMC9608075
OpenAlexW4297008497

What OpenQuestion holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.