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

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..

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