Stereoselective synthesis of novel 2'-(S)-CCG-IV analogues as potent NMDA receptor agonists.

Autor: Maolanon A; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, DK, 2100, Copenhagen, Denmark., Papangelis A; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, DK, 2100, Copenhagen, Denmark., Kawiecki D; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, DK, 2100, Copenhagen, Denmark., Mou TC; Division of Biological Sciences, University of Montana, Missoula, MT, 59812, USA; Center for Biomolecular Structure and Dynamics, University of Montana, Missoula, MT, 59812, USA., Syrenne JT; Division of Biological Sciences, University of Montana, Missoula, MT, 59812, USA; Center for Biomolecular Structure and Dynamics, University of Montana, Missoula, MT, 59812, USA; Center for Structural and Functional Neuroscience, University of Montana, Missoula, MT, 59812, USA., Yi F; Division of Biological Sciences, University of Montana, Missoula, MT, 59812, USA; Center for Biomolecular Structure and Dynamics, University of Montana, Missoula, MT, 59812, USA; Center for Structural and Functional Neuroscience, University of Montana, Missoula, MT, 59812, USA., Hansen KB; Division of Biological Sciences, University of Montana, Missoula, MT, 59812, USA; Center for Biomolecular Structure and Dynamics, University of Montana, Missoula, MT, 59812, USA; Center for Structural and Functional Neuroscience, University of Montana, Missoula, MT, 59812, USA., Clausen RP; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, DK, 2100, Copenhagen, Denmark. Electronic address: rac@sund.ku.dk.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2021 Feb 15; Vol. 212, pp. 113099. Date of Electronic Publication: 2020 Dec 18.
DOI: 10.1016/j.ejmech.2020.113099
Abstrakt: We developed a versatile stereoselective route for the synthesis of new 2'-(S)-CCG-IV analogues. The route allows for late stage diversification and thereby provides access to a great variety of conformationally restricted cyclopropyl glutamate analogues. A selection of the 2'-(S)-CCG-IV analogues were evaluated using two-electrode voltage-clamp electrophysiology at recombinant GluN1/GluN2A-D receptors, demonstrating that agonists can be developed with GluN2 subunit-dependent potency and agonist efficacy. We also describe a crystal structure of the GluN2A agonist binding domain in complex with 2'-butyl-(S)-CCG-IV that determines the position of 2'-substituents in (S)-CCG-IV agonists in the glutamate binding site and provides further insight to the structural determinants of their agonist efficacy. The stereoselective synthesis described here enables versatile and straight-forward modifications to diverse analogues of interest for the development of potent subtype-specific NMDA receptor agonists and other applications.
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Kasper B. Hansen is the principal investigator on a research grant from Janssen Research and Development to University of Montana.
(Copyright © 2020 Elsevier Masson SAS. All rights reserved.)
Databáze: MEDLINE
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