CCKAR

Cholecystokinin is the peptide hormone and neuropeptide that coordinates postprandial digestion - stimulating gallbladder contraction, pancreatic enzyme secretion, and gastric emptying inhibition - while signaling satiety to the brain via vagal afferents. It is the endogenous ligand for both CCKAR (CCK1R, peripheral GI actions) and CCKBR (CCK2R, CNS and gastric actions). Sincalide (CCK-8 sulfate) is FDA-approved as a diagnostic agent. CCK biology is the foundation for CCKAR-targeted satiety scaffolds and CCKBR-targeted radiopharmaceuticals for GI neuroendocrine tumors.

CCK is encoded on chromosome 3p22.1, processed from a 115-aa prepro-CCK precursor by prohormone convertases PC1/3 and PC2 at paired basic residues. Tissue-specific processing generates multiple bioactive forms: CCK-83, CCK-58, CCK-33, CCK-22, and CCK-8. The active core is CCK-8S (Asp-Tyr(SO3H)-Met-Gly-Trp-Met-Asp-Phe-NH2) - the sulfotyrosine at position 2 and the C-terminal amide are essential. CCK shares the C-terminal pentapeptide Gly-Trp-Met-Asp-Phe-NH2 with gastrin, accounting for cross-receptor activity at CCKBR. CCKAR requires the sulfotyrosine for high-affinity binding (Kd ~1 nM for CCK-8S; 500-1000-fold weaker for unsulfated forms); CCKBR binds sulfated and non-sulfated CCK equally and accommodates gastrin. Postprandial plasma CCK rises 5-8-fold from ~1 pM baseline, peaking at 5-8 pM within 15-30 minutes. Half-life is ~1-5 minutes in plasma, limiting therapeutic use of native peptide. Primary secretion is from enteroendocrine I-cells in duodenum and proximal jejunum; CNS expression is prominent in cortex, hippocampus, and hypothalamus where CCK acts as a neuromodulator for satiety, anxiety, memory, and pain. CCK1R knockout mice show impaired satiety and potentiated ghrelin responses.

Sincalide (CCK-8 sulfate, IV, 0.02-0.04 mcg/kg) is FDA-approved for gallbladder cholescintigraphy and pancreatic exocrine stimulation testing. No CCK agonist or antagonist is approved for obesity, GI motility, or psychiatric indications. GI181771X (selective CCKAR agonist) failed Phase 2 for obesity - a cautionary translational gap. Netazepide (YF476, CCKBR antagonist) reduced type I gastric NETs by ~50% in Phase 2 and is in active development. [177Lu]DOTA-CCK2R dimers for radionuclide therapy of small cell lung cancer and MTC are in Phase 1/2 as of 2025. For peptide research, the tractable recipes are: sulfotyrosine replacement in CCK-8S with phosphotyrosine or (p-sulfo)phenylalanine to improve synthetic accessibility while preserving CCKAR selectivity via the Arg197^ECL2 salt bridge; fatty acid-conjugated CCK-8 analogs (analogous to NN9056, ~110 h half-life in preclinical models) for sustained satiety through vagal CCKAR activation; CCK/GLP-1 hybrid peptides that combine CCK-8 C-terminus with GLP-1 N-terminus for synergistic weight loss, informed by Phase 2 data showing superior reduction vs. GLP-1 monotherapy; and DOTA/NOTA-chelated CCK-8 truncations with D-amino acid stabilization for CCKBR-targeted radiopharmaceuticals in MTC and gastric NET.