Developing New 4-PIOL and 4-PHP Analogues for Photoinactivation of γ-Aminobutyric Acid Type A Receptors

[en] The critical roles played by GABAA receptors as inhibitory regulators of excitation in the central nervous system has been known for many years. Aberrant GABAA receptor function and trafficking deficits have also been associated with several diseases including anxiety, depression, epilepsy, and insomnia. As a consequence, important drug groups such as the benzodiazepines, barbiturates, and many general anesthetics have become established as modulators of GABAA receptor activity. Nevertheless, there is much we do not understand about the roles and mechanisms of GABAA receptors at neural network and systems levels. It is therefore crucial to develop novel technologies and especially chemical entities that can interrogate GABAA receptor function in the nervous system. Here, we describe the chemistry and characterization of a novel set of 4-PIOL and 4-PHP analogues synthesized with the aim of developing a toolkit of drugs that can photoinactivate GABAA receptors. Most of these new analogues show higher affinities/potencies compared with the respective lead compounds. This is indicative of cavernous areas being present near their binding sites that can be potentially associated with novel receptor interactions. The 4-PHP azide-analogue, 2d, possesses particularly impressive nanomolar affinity/potency and is an effective UV-inducible photoinhibitor of GABAA receptors with considerable potential for photocontrol of GABAA receptor function in situ. © 2019 American Chemical Society.

Disciplines :

Pharmacy, pharmacology & toxicology

Author, co-author :

Mortensen, Martin; Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London, WC1E 6BT, United Kingdom

Krall, Jacob; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, Copenhagen, DK-2100, Denmark

Kongstad, Kenneth Thermann; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, Copenhagen, DK-2100, Denmark

Brygger, Benjamin M.; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, Copenhagen, DK-2100, Denmark

Lenzi, Ombretta; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, Copenhagen, DK-2100, Denmark

Francotte, Pierre ; Université de Liège - ULiège > Département de pharmacie > Chimie pharmaceutique

Sørensen, Troels E.; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, Copenhagen, DK-2100, Denmark

Nielsen, Birgitte; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, Copenhagen, DK-2100, Denmark

Jensen, Anders A.; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, Copenhagen, DK-2100, Denmark

Smart, Trevor G.; Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London, WC1E 6BT, United Kingdom

Frølund, Bente; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, Copenhagen, DK-2100, Denmark

Language :

English

Title :

Developing New 4-PIOL and 4-PHP Analogues for Photoinactivation of γ-Aminobutyric Acid Type A Receptors

Publication date :

20 November 2019

Journal title :

ACS Chemical Neuroscience

ISSN :

1948-7193

Publisher :

American Chemical Society

Volume :

Issue :

Pages :

4669

Peer reviewed :

Peer reviewed

Funders :

LundbeckfondenNovo Nordisk UK Research FoundationLeverhulme Trust

Available on ORBi :

since 20 May 2020

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