Allostery-driven G protein selectivity in the adenosine A1 receptor

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The adenosine A1 receptor (A1R), like many G protein-coupled receptors, GPCRs, is potentially a high value drug target for conditions, such as glaucoma, type 2 diabetes mellitus, pain, epilepsy and cerebral ischemia, and while drugs for these conditions exist, nevertheless there remain clear unmet clinical needs in these areas. However, the A1R has been classified as undruggable because of serious side effects intrinsically linked to the target. The problem arises because the A1R activates multiple G proteins. In the CNS, A1Rs inhibit synaptic transmission, induce neuronal hyperpolarization and cause sedation, while in the cardiorespiratory system A1Rs slow the heart (bradycardia) and contribute to reducing blood pressure (hypotension), and depressed respiration (dyspnea).
The compound BnOCPA, identified through serendipity, has totally shifted the paradigm as it only activates the G protein Gob (the CNS effects), through which it confers pain relief in vivo. It does not activate Goa so there are no cardiovascular side effects. BnOCPA now allows us to propose a rational approach to designing G protein selective A1R agonists. Our strategy is based on the observation that BnOCPA spans both the orthosteric and an allosteric binding site, though it only slightly impinges on this allosteric site. We will therefore study combinations of orthosteric and allosteric modulators to find combinations that alter the bias of the A1R. The results will be interpreted through extensive supervised molecular dynamics simulations of equilibrium binding, ligand (un)binding pathways and of the dynamic interaction pathway between the A1R:agonist complex and the relevant G proteins. The nature of the interactions will also be determined through mutagenesis and chemical modification of the oxybenzyl (BnO) group of BnOCPA (the group that confers selective binding to Gob). These results will feed into the design of novel BnOCPA analogues with rationally designed G protein selectivity.