Opioids are widely prescribed as analgesics but they are not always the best course of treatment due to adverse side effects and addictive properties. Therefore, a new class of smarter painkillers, drugs that specifically target therapeutic signalling pathways while avoiding others associated with adverse effects are highly desirable. An alternative route to finding more selective agonists for use as painkillers is through downstream signalling pathway associated with the activation of M2 and M4 muscarinic receptors. Similar to opioid receptors, activation of M2 and M4 receptors results in the coupling to the Gi/o family of G-proteins, inhibition of adenylate cyclase, reduction in cAMP and a decrease in neurotransmitter release.<br/>Preliminary data from both heterogeneous expression systems and ex vivo studies for several efficacious agonists, which caused substantial inhibition of cAMP and little stimulation of inositol phosphate accumulation, will be presented. Data strongly indicate that these compounds have much greater efficacy for M2 and M4 Gi/o signalling than for M1, M3 and M5 Gq signalling. These compounds, in contrast to carbachol, only inhibit production of cAMP at M2 and M4 receptors displaying absolute Gi/o bias. Similarly, at M1 and M3 receptors, these compounds only inhibit cAMP production.<br/>Simulation of molecular dynamics has revealed specific interaction of these biased agonists in the orthosteric binding site and specific conformation of the M2 receptor. In comparison with balanced agonists carbachol and iperoxo, these agonists bind deeper in the orthosteric binding site. The most striking difference is the absence of hydrogen bonding to N404 in TM6. Instead, they interact with W400 one turn deeper in TM6 via a combination of various weaker interactions.

Development of selective M2 and M4, Gi/o-biased muscarinic agonists: A potential therapeutic alternative to opioid analgesics

ACS Spring 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.