The Synthesis of Biologically Active Small-Molecule Antagonists of PAC1R as Potential Therapeutics for Migraine, Chronic Pain, and Anxiety Disorders

Abstract

The pituitary adenylate cyclase-activating polypeptide 1 receptor (PAC1R) is a a member of the vasoactive intestinal peptide (VIP)/secretin/glucagon family of G protein-coupled receptors (GPCRs) which has recently sparked interest within the scientific community for its extensive involvement in the central and peripheral nervous systems. PAC1R can activate a myriad of signaling transduction pathways, including adenylyl cyclase, phospholipase C, MEK/ERK, and Akt pathways which regulate several physiological systems to maintain functional homeostasis. Additionally, it has recently been determined that maladaptive signaling between the pituitary adenylate cyclase-activating polypeptide (PACAP) and PAC1R can lead to a variety of physiological abnormalities such as chronic pain, migraine, anxiety, and PTSD. Given the crucial role of PACAP in maintaining homeostatic processes and its involvement with these disorders in the body, the peptide has emerged as a valuable pharmacological target. Recent research has suggested that PAC1R antagonism can correct maladaptive signaling between PACAP and PAC1R that contributes to pain and stress-related behaviors. Unfortunately, design of PAC1R-selective antagonists has been challenging due to a lack of information regarding the structure and mechanisms of the receptor. This work is a collaborative effort that involves the synthesis and biological evaluation of small molecule antagonists of PAC1R in an attempt to develop a viable therapeutic for chronic pain, migraine, anxiety, and PTSD