Design, Synthesis And Biological Evaluation Of Small Molecule Allosteric Modulators Of Pac1 Receptor For Treatment Of Chronic Pain, Migraine And Neurological Disorders

Pituitary adenylate cyclase activating peptide (PACAP) and its cognate PAC1 receptor (PAC1R) have been shown to play important roles in central and peripheral nervous systems such as neuroprotection, vasodilation, and cell proliferation and differentiation. PACAP/PAC1R neurotrophic signaling events can be beneficial in mitigation of injury-induced cell damages, neuroinflammation, and disease-related degeneration. As examples, PACAP has been shown to mitigate or delay neural damage progression associated with neurodegenerative diseases like Alzheimer’s, Huntington’s and Parkinson’s diseases. A targeted PAC1R positive allosteric modulator would facilitate or enhance PACAP/PAC1R activation, which could serve as therapeutic for neuroinjury-related disorders and neurodegenerative diseases.In contrast, the chronic long-term effect of PACAP/PAC1R signaling appears to induce maladaptive neuroplasticity linked to stress-related behavioral disorders such as chronic pain, migraines, and anxiety-like psychopathologies. Chronic stress paradigms have been shown to increase PACAP expression and altered PACAP levels in the blood have been associated with post-traumatic stress disorder (PTSD). Therefore, PAC1R antagonism to block downstream signaling, especially ERK pathways, may be important for therapeutics. Through a combination of molecular docking, organic synthesis, and biological assays, we have identified small molecule compounds with significant modulatory effects on PAC1 receptor signaling: pyrazolone derivatives that enhance PACAP-induced PAC1R activation, and acyl hydrazide derivatives that inhibit PACAP/PAC1 receptor-induced ERK activation. Biological assays confirmed these molecules’ efficacy in selectively modulating PAC1 receptor functions. Additionally, comprehensive structure-activity relationship (SAR) studies have highlighted critical structural motifs, providing valuable insights into optimizing receptor-ligand interactions for future therapeutic development.