A negative allosteric modulator modulates GABAB-receptor signalling through GB2 subunits

The Biochemical Journal
Bing SunJianfeng Liu

Abstract

An γ-aminobutyric acid type B (GABAB)-receptor mediates slow and prolonged synaptic inhibition in the central nervous system, which represents an interesting target for the treatment of various diseases and disorders of the central nervous system. To date, only one activator of the GABAB-receptor, baclofen, is on the market for the treatment of spasticity. Inhibitors of the GABAB-receptor, such as antagonists, show anti-absence seizure activity and pro-cognitive properties. In a search for allosteric compounds of the GABAB-receptor, although several positive allosteric modulators have been developed, it is only recently that the first negative allosteric modulator (NAM), CLH304a (also named Compound 14), has been reported. In the present study, we provide further information on the mechanism of action of CLH304a, and also show the possibility of designing more NAMs, such as CLH391 and CLH393, based on the structure of CLH304a. First we show that CLH304a inhibits native GABAB-receptor activity in cultured cerebellar granular neurons. We then show that CLH304a has inverse agonist properties and non-competitively inhibits the effect of agonists, indicating that it binds at a different site to GABA. The GABAB-receptor is a mandator...Continue Reading

Citations

Dec 3, 2016·Nature·Jean-Philippe Pin, Bernhard Bettler
Apr 21, 2017·Molecular Pharmacology·Shuai XiaJianfeng Liu
Mar 23, 2017·PloS One·Thibaud FreydMari Gabrielsen
Apr 3, 2021·Neuropharmacology·Alessandra PorcuM Paola Castelli
Oct 16, 2020·Journal of Molecular Biology·Yoojoong KimYunje Cho

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