Dr. Porreca was also a 2007 MRF grantee. Read his completed research.

FINAL REPORT: PACAP Antagonists as Novel Migraine Therapies

Read the journal article here.

Summary

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 PACAP_6—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” PACAP_6—38 peptide only produced low potency antagonism at concentrations approaching 1 µM. We thus hypothesize that the observed antagonist activity of PACAP_6—38 in published studies may be mediated via VPAC₁ and VPAC₂ receptors.

Conclusion:

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).

Unanswered Questions:

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.