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

LM Williams; X He; TM Vaid; A Abdul-Ridha; AR Whitehead; PR Gooley; RAD Bathgate; SJ Williams; DJ Scott

Journal article

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

LM Williams, X He, TM Vaid, A Abdul-Ridha, AR Whitehead, PR Gooley, RAD Bathgate, SJ Williams, DJ Scott

Pharmacology Research and Perspectives | JOHN WILEY & SONS LTD | Published : 2019

DOI: 10.1002/prp2.455

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Abstract

α 1A - and α 1B -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). α 1A - and α 1B -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 α 1 -ARs. Here, using thermostabilized, purified, α 1A - and α 1B -ARs, we sought to identify the benzodiazepine binding site and modulatory mechanism to inform t..

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University of Melbourne Researchers

Paul Gooley Author

Ross Bathgate Author

Spencer Williams Author

Daniel Scott Author

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Awarded by Australian 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