An alternative route to finding selective agonists for use as pain killers devoid of the side effects of opioids is through downstream signalling pathway associated with the activation of M2 and M4 muscarinic receptors. Similar to the analgesia mediated by opioid receptors, activation of M2 receptors leads to activation of Gi/o G-proteins and consequent decrease in cAMP which causes attenuation in the activity of tetrodotoxin-resistant voltage-gated sodium channels. The βγ dimers released from activated Gi/o G-proteins activate inwardly- rectifying potassium channels. A decrease in the activity of sodium channels and activation of potassium channels result in a decrease in excitability of nociceptive sensory neurons. 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 indicates 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. 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.

Synthesis of biased muscarinic agonists as a smarter class of analgesics with lower adverse effects

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