Medicinal Chemistry & Chemical Biology, Short talk
MC-014

Synthesis and characterization of an adenosine A1 receptor agonist with non-opioid analgesic properties based on Gα signaling bias

B. Preti1, M. Leuenberger1, M. Lochner1*
1Institute of Biochemistry and Molecular Medicine, University of Bern

The four adenosine receptor subtypes (A1, A2A, A2B, and A3) belong to the of G protein-coupled receptors (GPCRs). The purinergic signaling system plays an important role both in the central (CNS) and peripheral nervous system (PNS), but it is widely operational in other human tissues. For this reason, adenosine receptors (ARs) are linked to oncological, cardiovascular, neurological, respiratory and inflammatory disorders. Significant efforts were made by companies to develop agonist or antagonists against specific AR subtypes in order to treat diseases in the aforementioned areas. So far, no such drugs have been approved. GPCRs are one of the prominent target classes in medicinal chemistry and cover one third of all medicines, however, adenosine receptors (ARs) have particularly suffered as drug targets due to their propensity to couple to different Gα subunits, activating several downstream signaling pathway and therefore causing unwanted side effects. In the case of A1R, its activation can cause cardiorespiratory side effects. The therapeutic limitations of A1R due to its unselective coupling could be overcome by developing biased agonists: compounds that selectively activate one intracellular signaling pathway over others.

Among the compounds synthesized in our laboratory, several showed A1R subtype-selective agonist activity. Interestingly, compound BnOCPA stood out in that it is able to activate one particular G protein-mediated signaling pathway in a highly potent and selective manner. This exclusive Gα signaling bias was validated for the first time in vivo. BnOCPA properties were studied in a rat model of chronic neuropathic pain and showed that it is a potent and powerful analgesic without causing any side effects such as bradycardia, hypotension, respiratory depression, tolerance, dependence and abuse potential, as most opioid drugs. Therefore, BnOCPA represents a powerful to  investigate biased GPCR signaling and it is also a lead structure of a new first-in-class analgesic drug.

[1] bioRxiv: doi.org/10.1101/2020.04.04.023945
[2] J. Med. Chem. 2016, 59, 3, 947–964