Project Summary Chronic use of commonly used migraine therapies, such as triptans and opioids, can lead to medication overuse headache (MOH). This is a paradoxical increase in severity of migraine-associated symptoms and headaches which are refractory to other treatments. Currently, the first-line treatment for MOH is drug cessation. However, during this abstinence period, patients continue to suffer from severe migraine, and in the case of opioids from withdrawal; and a majority of MOH patients return to these medications within the first year. Targeted therapies specifically for MOH would result in better headache management and increased patient quality of life. Our lab has recently investigated mechanisms of MOH. Through an unbiased peptidomic screen, our lab identified the neuropeptide, pituitary adenylate cyclase activating polypeptide (PACAP), as being augmented in preclinical models of chronic migraine and MOH. Our preliminary data suggests that antagonism of PAC1, a high affinity PACAP receptor, inhibits allodynia and aura associated with MOH. However, the PACAPergic system is relatively understudied and there is a lack of selective ligands to the PAC1 receptor. Currently there are only 3 PAC1 inhibitors, and two of them are peptides. Although the small molecule antagonist, PA8, is effective in our models, it has only moderate potency. The objective of this proposal is to develop novel PAC1 receptor antagonists for the treatment of MOH. This grant aims to develop a collaboration between the Pradhan, Majumdar, and Katritch labs. The Pradhan, Katritch and Majumdar labs have expertise in PAC1 pharmacology/behavioral models, computational modeling, medicinal chemistry, pharmacology and structure- based design of drug molecules. In Aim 1, the Katritch group will utilize a combination of virtual ligand screening, and their new platform based on V-SYNTHES on structures of PAC1 to identify novel molecules with antagonistic activity at this receptor. As a second avenue, we also propose to optimize the potency of PA8, using structure- based design, and discover new compounds with improved in vivo activity compared to the parent (Katritch/Majumdar). In Aim 2 we will pharmacologically characterize promising lead compounds. We will evaluate PAC1 antagonists for potency and selectivity in cAMP assays in transfected cell lines (Pradhan) as well as in vitro ADME and pharmacokinetic analysis in plasma and brain (Majumdar). Finally, in Aim 3 we will test the most promising lead PAC1 antagonists in models of MOH and migraine. We will also perform preliminary tests exploring adverse CNS effects of lead compounds. This R61 mechanism will allow us to establish a multidisciplinary and collaborative team to identify and characterize promising lead candidates targeting the PAC1 receptor for the treatment of MOH.

Project Narrative Medication overuse headache (MOH) develops when migraine patients overuse acute migraine medications, resulting in a paradoxical increase in headache frequency and severity. Our lab has identified a novel mechanism for the treatment of MOH, by inhibiting the PAC1 receptor. The aim of this proposal is to develop novel PAC1 receptor blockers that can be used as a novel therapy for MOH.