Diazepam is not a direct allosteric modulator of alpha(1)-adrenoceptors, but modulates receptor signaling by inhibiting phosphodiesterase-4

Lisa M Williams; Xiaoji He; Tasneem M Vaid; Alaa Abdul-Ridha; Alice R Whitehead; Paul R Gooley; Ross AD Bathgate; Spencer J Williams; Daniel J Scott

Journal article

Diazepam is not a direct allosteric modulator of alpha(1)-adrenoceptors, but modulates receptor signaling by inhibiting phosphodiesterase-4

Lisa M Williams, Xiaoji He, Tasneem M Vaid, Alaa Abdul-Ridha, Alice R Whitehead, Paul R Gooley, Ross AD Bathgate, Spencer J Williams, Daniel J Scott

PHARMACOLOGY RESEARCH & PERSPECTIVES | JOHN WILEY & SONS LTD | Published : 2019

DOI: 10.1002/prp2.455

Download PDF

Abstract

α1A- and α1B-adrenoceptors (ARs) are G protein-coupled receptors (GPCRs) that are activated by adrenaline and noradrenaline to modulate smooth muscle contraction in the periphery, and neuronal outputs in the central nervous system (CNS). α1A- and α1B-AR are clinically targeted with antagonists for hypertension and benign prostatic hyperplasia and are emerging CNS targets for treating neurodegenerative diseases. The benzodiazepines midazolam, diazepam, and lorazepam are proposed to be positive allosteric modulators (PAMs) of α1-ARs. Here, using thermostabilized, purified, α1A- and α1B-ARs, we sought to identify the benzodiazepine binding site and modulatory mechanism to inform the design of s..

View full abstract

University of Melbourne Researchers

Paul Gooley Author Biochemistry and Pharmacology

Daniel Scott Author Florey Department of Neuroscience and Mental Health

Spencer Williams Author Chemistry

Ross Bathgate Author Florey Department of Neuroscience and Mental Health

Related Projects (3)

STABILISING G PROTEIN-COUPLED RECEPTORS FOR DRUG DISCOVERY

Prescription drugs targeting human proteins called GPCRs are sold as effective treatments for many diseases. However, there are over 800 dif..

BREAKING IT DOWN: DISSECTING THE MECHANISM AND EXPLORING NEW INHIBITION STRATEGIES FOR POLYSACCHARIDE CLEAVING ENZYMES

Mannose, a common carbohydrate building block, is present in a wide variety of complex polysaccharides including energy storage polymers and..

NOVEL APPROACHES TO UNDERSTANDING PEPTIDE G-PROTEIN-COUPLED RECEPTOR ACTIVATION

G protein-coupled receptors (GPCRs) are proteins that exist on every human cell, where they sense, and respond to environmental stimuli. Bec..

Grants

Awarded by Australian Research Council

Awarded by National Health and Medical Research Council

Funding Acknowledgements

Australian Research Council, Grant/Award Number: FT130100103, LE120100022; National Health and Medical Research Council, Grant/Award Number: 1081801, 1099692, 1137179, 1141034; Victorian Government's Operational Infrastructure Support Program