Selective activation of Gαob by an adenosine A1 receptor agonist elicits analgesia without cardiorespiratory depression

Abstract

One third of all medicines act at G protein-coupled receptors (GPCRs). However, the identification of new therapeutic GPCR targets is limited by a fundamental property of GPCRs: their propensity to couple to different G protein alpha subunits (Gα) leading to multiple downstream cellular effects. This is especially the case for adenosine A1 receptors (A1Rs), the activation of which results in unwanted cardiorespiratory effects, severely limiting their clinical potential. We have discovered that the novel A1R agonist, BnOCPA, unlike typical A1R agonists, has a unique and highly selective Gα activation preference. Moreover, we found that BnOCPA is a potent and powerful analgesic without causing bradycardia, hypotension or respiratory depression. BnOCPA thus demonstrates a hitherto unknown Gα-selective activation of the native A1R, sheds new light on the fundamentals of GPCR signalling, and reveals new possibilities for the development of novel therapeutics based on the far-reaching concept of biased agonism. Abbreviated summary:We describe the selective activation of an adenosine A1 receptor-mediated intracellular pathway that provides potent analgesia in the absence of cardiorespiratory depression, paving the way for novel medicines based on the far-reaching concept of biased agonism. Wall et al., Main Text and Figures4 Main text: G protein-coupled receptors (GPCRs) are the targets of many FDA-approved drugs (1). However, the promiscuity with which they couple to multiple intracellular signalling cascades leads to unwanted side effects, and limits both the range of GPCRs suitable for drug-targeting, and the number of conditions for which treatments could be developed (2). The four GPCRs for the purine nucleoside adenosine have particularly suffered as drug targets due to their promiscuous coupling, despite their potential for treating many pathological conditions including cancer, cardiovascular, neurological and inflammatory diseases (3-5). For example, activation of the widely-distributed adenosine A1 receptor (A1R) with currently available agonists elicits multiple actions in both the central nervous system (CNS), such as the inhibition of synaptic transmission and neuronal hyperpolarization, and in the cardiorespiratory system through slowing the heart (bradycardia), reducing blood pressure (hypotension) and affecting respiration (dyspnea) (5-8). These multiple effects severely limit the prospects of A1R agonists as life-changing medicines, despite their potential in a wide range of clinical conditions including pain, epilepsy and cerebral ischemia (5,(9)(10)(11).

Multisite Model of Allosterism for the Adenosine A1 Receptor

“…VCP746 showed bias towards the cAMP pathway relative to (probably G protein-dependent 74,75 ) ERK1/2 signalling, and no observable effect on heart rate in isolated rat atria 33 . SAR studies 33,76 determined that the 3-(trifluoromethyl)phenyl substituent is important for the allostericallydriven A 1 R bias, while the best linker length between the two pharmacophores (Figure 1) is six carbon atoms.…”

International Union of Basic and Clinical Pharmacology. CXII: Adenosine Receptors: A Further Update

“…However, in most cases, the precise G protein-dependent or independent pathways involved in the salutary effects of adenosine agonists are unexplored. Recently, an A 1 AR agonist that was reported to selectively activate G ob versus the other five G α i/o subtypes and without β -arrestin recruitment was discovered ( Wall et al, 2020 ). It appears to act as a potent analgesic without sedation or cardiorespiratory depression.…”

Molecular Simulations and Drug Discovery of Adenosine Receptors

“…The AR biased agonism has been explored by MD simulations. By combining MD simulations, Gαi/o subunit- and β-arrestin-specific cellular signaling assays, Wall et al [ 106 ] identified that the A 1 AR-selective agonist, BnOCPA, was a biased agonist in exclusively activating the G ob protein. MD simulations were applied on the A 1 AR bound by the biased agonist BnOCPA, neutral agonists ADO and HOCPA and an antagonist PSB36.…”

“…Wall et al [ 106 ] discovered biased agonist BnOCPA of A 1 AR that favors G ob over other G protein subtypes and hence produces analgesic effects without sedation, bradycardia and hypotension. MD simulations revealed the BnOCPA binding modes in the receptor.…”