Development of tricyclic N-benzyl-4-hydroxybutanamide derivatives as inhibitors of GABA transporters mGAT1-4 with anticonvulsant, antinociceptive, and antidepressant activity.
Amides
/ chemical synthesis
Analgesics
/ chemical synthesis
Anticonvulsants
/ chemical synthesis
Antidepressive Agents
/ chemical synthesis
Dose-Response Relationship, Drug
Drug Development
GABA Uptake Inhibitors
/ chemical synthesis
Humans
Molecular Structure
N-Acetylglucosaminyltransferases
/ antagonists & inhibitors
Structure-Activity Relationship
Anticonvulsant activity
Antidepressant-like properties
Antinociceptive activity
GABA transporter
GAT inhibitors
Molecular docking
Molecular dynamics
N-benzylamides
[(3)H]GABA uptake
mGAT1
mGAT2
mGAT3
mGAT4
Journal
European journal of medicinal chemistry
ISSN: 1768-3254
Titre abrégé: Eur J Med Chem
Pays: France
ID NLM: 0420510
Informations de publication
Date de publication:
05 Oct 2021
05 Oct 2021
Historique:
received:
21
11
2020
revised:
20
04
2021
accepted:
22
04
2021
pubmed:
21
5
2021
medline:
7
8
2021
entrez:
20
5
2021
Statut:
ppublish
Résumé
γ-Aminobutyric acid (GABA) neurotransmission has a significant impact on the proper functioning of the central nervous system. Numerous studies have indicated that inhibitors of the GABA transporters mGAT1-4 offer a promising strategy for the treatment of several neurological disorders, including epilepsy, neuropathic pain, and depression. Following our previous results, herein, we report the synthesis, biological evaluation, and structure-activity relationship studies supported by molecular docking and molecular dynamics of a new series of N-benzyl-4-hydroxybutanamide derivatives regarding their inhibitory potency toward mGAT1-4. This study allowed us to identify compound 23a (N-benzyl-4-hydroxybutanamide bearing a dibenzocycloheptatriene moiety), a nonselective GAT inhibitor with a slight preference toward mGAT4 (pIC
Identifiants
pubmed: 34015586
pii: S0223-5234(21)00361-5
doi: 10.1016/j.ejmech.2021.113512
pii:
doi:
Substances chimiques
Amides
0
Analgesics
0
Anticonvulsants
0
Antidepressive Agents
0
GABA Uptake Inhibitors
0
MGAT1 protein, human
EC 2.4.1.-
MGAT4A protein, human
EC 2.4.1.-
N-Acetylglucosaminyltransferases
EC 2.4.1.-
alpha-1,6-mannosyl-glycoprotein beta-1,2-N-acetylglucosaminyltransferase
EC 2.4.1.143
beta-1,4-mannosyl-glycoprotein beta-1,4-N-acetylglucosaminyltransferase
EC 2.4.1.144
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
113512Informations de copyright
Copyright © 2021 Elsevier Masson SAS. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.