Structure-based evolution of potent non-opioid analgesics

• Applicant: Professor Dr. Peter Gmeiner
• Subject Area: Pharmacy
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 529913688

The treatment of pain by opioids is difficult because they induce severe side effects. Hence, the great demand for effective and safe pain therapeutics has inspired a search for nonopioid GPCR ligands with analgesic properties. Aiming to discover such molecules for the a2A-adrenergic receptor (a2AAR), we could show that a structure-based approach is very valuable allowing us access to novel chemotypes with partial agonist activity, Gi preference, and a lack of internalization. Interestingly, the new lead compounds showed analgesic activity and reduced sedative side effects in vivo. The proposed Reinhart Koselleck Project aims to discover Gi-biased partial agonists based on high-resolution GPCR structures. To make the compounds highly efficacious, we will follow a multi-target approach addressing the adrenergic a2A-receptor together with the serotonin 5-HT1AR or the tachykinin NK1 receptor. Deciphering the importance of non-canonical receptor-ligand interactions by cryo-EM, mutational analysis and MD simulations, we aim to create an understanding of the key principles of biased agonism. Our findings will contribute to both the elaboration of powerful integrative medicinal chemistry strategies and the evolution of effective and safe analgesics. Our research program will integrate a virtual docking campaign of ultra-large libraries (more than 400 million compounds) towards three different nonopioid pain targets (a2AAR, 5-HT1AR, and NK1R). The identification of new chemotypes with multi-target properties, early hit-to-lead optimization, and cryo-EM studies will be key to an understanding of biased agonism and a structure-guided advanced lead optimization leading us to drug-like molecules with promising analgesic properties.

• DFG Programme: Reinhart Koselleck Projects