pH-dependent opioid ligands - structural features and mechanisms underlying analgesic effects

• Applicant: Professor Dr. Christoph Stein
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells ; Anaesthesiology ; Pharmacology
• Term: from 2020 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 434131077

Pain treatment is a major challenge in medicine and public health. Conventional analgesic drugs produce detrimental side effects such as the central and intestinal actions of opioid receptor agonists (sedation, apnoea, addiction, nausea, constipation), and the gastrointestinal and cardiovascular effects of cyclooxygenase inhibitors. Such actions limit the applicability of available drugs and have contributed significantly to the current opioid crisis. Aiming at the elimination of side effects, we have recently developed a novel artificial intelligence-based concept exploiting the functional relevance of opioid receptors on peripheral sensory neurons, and the conformational dynamics of interactions between ligands and G-protein coupled receptors under pathological conditions. To selectively target opioid receptors in the acidic environment of injured tissue, our approach aims at reducing a ligand’s acid dissociation constant by introducing electronegative moieties in order to preclude the protonation of its tertiary amine (an essential prerequisite for opioid receptor activation) at normal pH (in brain and intestinal wall). Our prototype pH-dependent ligand NFEPP successfully reduced pain in animals with inflammatory tissue injuries, without eliciting central or intestinal adverse effects in healthy animals. However, detailed structural characteristics of ligand-receptor interactions or the cellular mechanisms underlying the analgesic actions of pH-dependent opioid ligands are unknown to date. The present project shall examine (i) which specific ligand moieties and opioid receptor amino acid residues are crucial in the modulation of ligand-receptor interactions by acidosis, (ii) how the acid dissociation constant of exogenous (fentanyl and derivatives) or endogenous (Met-enkephalin) opioid ligands influences G-protein coupling and heterotrimer dissociation into G-Protein subunits, and (iii) whether pH-dependent opioid ligands induce side effects in models of persistent pain in vivo.

• DFG Programme: Research Grants