Date of Award


Document Type


Degree Name

Doctor of Philosophy (PhD)



First Advisor

Matthias Brewer


Class B G-protein coupled receptors (GPCRs) are activated by the secretin/glucagon/VIP family of related peptides for physiological homeostasis. Importantly, the PAC1 and VPAC receptor subtypes, which recognize the pituitary adenylate cyclase activating peptide (PACAP) and vasoactive intestinal peptide (VIP), are involved in many central effects such as nociceptive sensitivity, learning/memory, and stress-associated behaviors. By targeting these receptors, small molecule antagonists that regulate signaling have therapeutic potential to mitigate maladaptive PACAP/PAC1 receptor signaling that may be contributory to a number of disorders including chronic pain, migraine and anxiety disorders including post-traumatic stress disorder. Identifying antagonists for the PAC1 receptor is complicated by the fact that there are no published full-length crystal structures of this receptor, which makes the rational design and development of small molecule therapeutics difficult. In spite of these challenges, several potent small molecule antagonists for the PAC1 receptor have been discovered and developed in the Brewer lab. Based on these scaffolds, we have performed extensive structure activity relationship studies to understand important motifs necessary for selective and potent binding at the PAC1 receptor. This work benefited from the collaboration with computational chemists and neuroscientists which aided in the discovery of the novel scaffolds through molecular modeling simulations and biological studies. Additionally, data from open field tests and elevated plus mazes confirm that pretreatment with our small molecule antagonists reduce PACAP-stimulated anxiety-like behavioral responses in rats.

This thesis will describe our work that led to the identification of three novel scaffolds that act as small molecule antagonists of the PAC1 receptor RJB145, RJB248, and JF214. These compounds effectively block PAC1 receptor signaling in in vitro assays at low micromolar concentrations (IC50≤10μM). RJB145 and JF214 have also been shown to mediate anxiety-like responses in rats in various behavioral models.



Number of Pages

321 p.

Available for download on Sunday, October 05, 2025