ADCYAP1R1 / PAC1R

PAC1 is a class B GPCR and the primary high-affinity receptor for PACAP-38 and PACAP-27 - neuropeptides with deep roles in stress response, neuroplasticity, and autonomic control. PAC1 is the most therapeutically significant node in the PACAP/VIP receptor family because of its selective expression in stress circuits (amygdala, hypothalamus, nucleus accumbens) and its causal links to PTSD, migraine, and neuropathic pain. Every scaffold targeting neuroinflammation, fear memory, or trigeminovascular activation intersects this card.

The receptor sits on chromosome 7p14.3 (~59 kb, 18 exons). Four splice isoforms generated by ICL3 cassette insertions define its pharmacology: the null isoform couples exclusively to Gs/cAMP/PKA; hop1 adds Gq/11 → PLC → IP3 → Ca²⁺ flux; hip impairs Gq while retaining Gs; hip-hop1 reduces both pathways. PACAP-38 and PACAP-27 bind PAC1 with sub-nM affinity - roughly 1000-fold higher than their affinity for VPAC1/2. PACAP(6-38), the N-terminally truncated fragment, is the canonical research antagonist. Highest expression: adrenal medulla (PACAP drives catecholamine release), amygdala, hippocampus, and hypothalamic nuclei. The rs2267735 intronic SNP associates with PTSD risk in women specifically, implicating isoform-level expression differences in sex-biased stress pathology.

No PAC1-targeting drug is approved. AMG 301, a monoclonal antibody against PAC1, failed Phase 2 episodic migraine - confirming target engagement but revealing endpoint or patient-selection gaps rather than mechanism failure. BAY 2686013 is an allosteric small-molecule antagonist with high PAC1/VPAC selectivity, currently preclinical. PA-915, a non-peptide orthosteric antagonist, produced antidepressant effects in mice lasting ~8 weeks from a single dose - a durability profile that has no parallel in the GPCR antagonist space and warrants close watching. For peptide scaffolds, the tractable recipes involve PACAP analogs with D-amino acid substitutions at positions 3–6 to block N-terminal receptor activation while retaining binding, cyclized PACAP fragments for PAC1 selectivity over VPAC1/2, and PACAP(6-38) derivatives as starting points for antagonist optimization. The hop1-selective signaling axis (Gq rather than Gs) is an underexplored fork: scaffolds that bias signaling away from cAMP toward Ca²⁺ may separate the receptor's analgesic effects from its stress-sensitizing ones.