학술논문
Development of a Dihydroquinoline-Pyrazoline GluN2C/2D-Selective Negative Allosteric Modulator of the N -Methyl-d-aspartate Receptor.
Document Type
Academic Journal
Author
D'Erasmo MP; Department of Chemistry, Emory University, Atlanta, Georgia 30322, United States.; Akins NS; Department of Chemistry, Emory University, Atlanta, Georgia 30322, United States.; Ma P; Department of Chemistry, Emory University, Atlanta, Georgia 30322, United States.; Jing Y; Department of Chemistry, Emory University, Atlanta, Georgia 30322, United States.; Swanger SA; Department of Pharmacology and Chemical Biology, Emory University, Atlanta, Georgia 30322, United States.; Sharma SK; Department of Chemistry, Emory University, Atlanta, Georgia 30322, United States.; Bartsch PW; Department of Chemistry, Emory University, Atlanta, Georgia 30322, United States.; Menaldino DS; Department of Chemistry, Emory University, Atlanta, Georgia 30322, United States.; Arcoria PJ; Department of Chemistry, Emory University, Atlanta, Georgia 30322, United States.; Bui TT; INMED, INSERM, Aix Marseille University, 13284 Marseille, France.; Pons-Bennaceur A; INMED, INSERM, Aix Marseille University, 13284 Marseille, France.; Le P; Department of Pharmacology and Chemical Biology, Emory University, Atlanta, Georgia 30322, United States.; Allen JP; Department of Pharmacology and Chemical Biology, Emory University, Atlanta, Georgia 30322, United States.; Ullman EZ; Department of Pharmacology and Chemical Biology, Emory University, Atlanta, Georgia 30322, United States.; Nocilla KA; Department of Pharmacology and Chemical Biology, Emory University, Atlanta, Georgia 30322, United States.; Zhang J; Department of Pharmacology and Chemical Biology, Emory University, Atlanta, Georgia 30322, United States.; Perszyk RE; Department of Pharmacology and Chemical Biology, Emory University, Atlanta, Georgia 30322, United States.; Kim S; Department of Pharmacology and Chemical Biology, Emory University, Atlanta, Georgia 30322, United States.; Acker TM; Department of Chemistry, Emory University, Atlanta, Georgia 30322, United States.; Taz A; Department of Chemistry, Emory University, Atlanta, Georgia 30322, United States.; Burton SL; Department of Chemistry, Emory University, Atlanta, Georgia 30322, United States.; Coe K; Janssen Research & Development, LLC, San Diego, California 92121, United States.; Fritzemeier RG; Department of Chemistry, Emory University, Atlanta, Georgia 30322, United States.; Burnashev N; INMED, INSERM, Aix Marseille University, 13284 Marseille, France.; Yuan H; Department of Pharmacology and Chemical Biology, Emory University, Atlanta, Georgia 30322, United States.; Liotta DC; Department of Chemistry, Emory University, Atlanta, Georgia 30322, United States.; Traynelis SF; Department of Pharmacology and Chemical Biology, Emory University, Atlanta, Georgia 30322, United States.
Source
Publisher: American Chemical Society Country of Publication: United States NLM ID: 101525337 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1948-7193 (Electronic) Linking ISSN: 19487193 NLM ISO Abbreviation: ACS Chem Neurosci Subsets: MEDLINE
Subject
Language
English
Abstract
Subunit-selective inhibition of N -methyl-d-aspartate receptors (NMDARs) is a promising therapeutic strategy for several neurological disorders, including epilepsy, Alzheimer's and Parkinson's disease, depression, and acute brain injury. We previously described the dihydroquinoline-pyrazoline (DQP) analogue 2a ( DQP-26 ) as a potent NMDAR negative allosteric modulator with selectivity for GluN2C/D over GluN2A/B. However, moderate (<100-fold) subunit selectivity, inadequate cell-membrane permeability, and poor brain penetration complicated the use of 2a as an in vivo probe. In an effort to improve selectivity and the pharmacokinetic profile of the series, we performed additional structure-activity relationship studies of the succinate side chain and investigated the use of prodrugs to mask the pendant carboxylic acid. These efforts led to discovery of the analogue ( S )-(-)- 2i , also referred to as ( S )-(-)- DQP-997 - 74 , which exhibits >100- and >300-fold selectivity for GluN2C- and GluN2D-containing NMDARs (IC 50 0.069 and 0.035 μM, respectively) compared to GluN2A- and GluN2B-containing receptors (IC 50 5.2 and 16 μM, respectively) and has no effects on AMPA, kainate, or GluN1/GluN3 receptors. Compound ( S )-(-)- 2i is 5-fold more potent than ( S )- 2a . In addition, compound 2i shows a time-dependent enhancement of inhibitory actions at GluN2C- and GluN2D-containing NMDARs in the presence of the agonist glutamate, which could attenuate hypersynchronous activity driven by high-frequency excitatory synaptic transmission. Consistent with this finding, compound 2i significantly reduced the number of epileptic events in a murine model of tuberous sclerosis complex (TSC)-induced epilepsy that is associated with upregulation of the GluN2C subunit. Thus, 2i represents a robust tool for the GluN2C/D target validation. Esterification of the succinate carboxylate improved brain penetration, suggesting a strategy for therapeutic development of this series for NMDAR-associated neurological conditions.