Raising Money for
2013 MRF Research Grantee
Dr. Porreca was also a 2007 MRF grantee. Read his completed research.
FINAL REPORT: PACAP Antagonists as Novel Migraine Therapies
Migraine patients experience pain and hypersensitivity that can be influenced by a number of neurotropic “factors” or “cytokines” (there are some 17 families of interleukins alone). These cytokines can have numerous roles, including promoting or reducing inflammation, or stimulating growth or differentiation. Generally speaking, most of the cell signaling molecules known to be associated with the migraine state are peptides; two well-known examples are brain-derived neurotrophic factor (BDNF) and Interleukin-6 (IL6). Steroid hormones such as estrogen are also known to play a role in migraine.
In our studies we examined the role of one of the less-well known signaling molecules involved in migraine, the secretin hormone Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP). PACAP has high affinity for the secretin receptor PAC1, and reduced affinity for the closely related receptors VPAC1 and VPAC2. PACAP is regarded as the principal ligand for PAC1. Vasoactive Intestinal Peptide (VIP) has a higher affinity for VPAC1 and VPAC2 and reduced affinity for PAC1. Since PACAP has been shown to induce migraines, we reasoned that a PACAP antagonist (PAC1 blocker) might have therapeutic value, or at least might help elucidate the role of PAC1 in the induction of the migraine state.
Although we were able to produce glycopeptide agonists (activators) for the PAC1, VPAC1 and VPAC2 receptors, attempts to design a PAC1 antagonist (a blocker) by removing the first few amino acids proved to be futile. We also could only demonstrate low potency antagonism at PAC1 with PACAP6—38, which is at odds with our current understanding of structure-activity relationships (SAR) for the PAC1 receptor.
Hypothesis vs. Finding:
We could not demonstrate antagonism at PAC1 with the truncated PACAP peptides, and even the “standard antagonist” PACAP6—38 peptide only produced low potency antagonism at concentrations approaching 1 µM. We thus hypothesize that the observed antagonist activity of PACAP6—38 in published studies may be mediated via VPAC1 and VPAC2 receptors.
The glycopeptide agonists (activators) based on PACAP show high potencies for PAC1 receptors (EC50’s ≈ 7—50 nM) with somewhat lower potencies for the VPAC1, receptor and very high potencies for the VPAC2 receptor (EC50’s ≈ 0.5 nM).
We are still compiling the data for a complete characterization of the truncated glycopeptides in antagonist mode with respect to VPAC1 and VPAC2.
What this research means to you:
We are now one step closer to being able to convert unstable peptide hormones such as PACAP into stable glycopeptide drugs with effects similar to the native peptides. Ultimately, we hope that a whole host of selective and non-toxic glycopeptide drugs that are based on neuropeptide hormones will eventually become available to treat CNS diseases such as migraine. Our current screening efforts with truncated PACAP peptides at VPAC1 and VPAC2 will reveal whether we are able to target these related receptors with antagonist drugs to treat migraine pain.