CCK Peptides with Combined Features of Hexa- and Tetrapeptide CCK-A Agonists

Abstract

Selective CCK-A agonist activity has been reported to induce satiety in a variety of animals, including man, and thereby suggests a therapeutic role for CCK in the management of obesity. To date, three general classes of CCK-A agonists have been reported, the full-length, sulfated hepta- and hexapeptides, a series of tetrapeptides, and most recently a series of benzodiazepines. The SAR of the hexa- and tetrapeptide classes suggests that the Hpa(SO(3)H) and Tac groups may not interact at the CCK-A receptor in the same location. However, the C-terminal dipeptide part of the hexapeptides and tetrapeptides appear to interact at the CCK-A receptor in a similar manner. Compound 7 (Hpa-Nle-Gly-Trp-Lys(Tac)-Asp-MePhe-NH(2)) derived from combining the features of the hexapeptides and the tetrapeptides has subnanomolar affinity and 3500-fold selectivity for CCK-A receptors. Compound 7 administered intraperitoneally produces potent, long-lasting reduction in food intake in rats and a corresponding weight loss when administered over nine consecutive days.

A GLP-1:CCK fusion peptide harnesses the synergistic effects on metabolism of CCK-1 and GLP-1 receptor agonism in mice

“…AC3174 (Amylin Pharmaceuticals) is a functional analog of exenatide ( Hargrove et al, 2007 ). AC170222 (Hpa-Nle-Gly-Trp-Lys(Tac)-Asp-NMePhe-NH 2 ; CPC Scientific, Sunnyvale, CA) is a CCKR1-selective peptide ( Pierson et al, 2000 ). C2816 is a fusion peptide of AC3174 linked to AC170222 via a mini-PEG linker (His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-[PEG4]-Nle-Gly-Trp-Lys(Tac)-Asp-NMePhe-NH 2 ); New England Peptide, Gardner, MA).…”

Synergistic metabolic benefits of an exenatide analogue and cholecystokinin in diet‐induced obese and leptin‐deficient rodents

“…A stabilized acetylated version of this molecule [Ac‐Asp‐Phe‐(CH 2 ‐SO 3 H)‐Met‐Gly‐Trp‐Met‐Asp‐Phe‐NH 2 ] was synthesized internally (hereafter referred to as Ac‐Y*‐CCK‐8) . A CCK1R‐selective agonist hexapeptide [Hpa‐Nle‐Gly‐Trp‐Lys(2‐tolylaminocarbonyl)‐Asp‐( N ‐methyl)Phe‐NH 2 ] referred to in previous reports as compound 7 , was synthesized internally using methods similar to those reported and is hereafter referred to as AC170222. AC170222 was reported to be 4000‐fold more selective for CCK1R versus CCK2R (Ki for CCK1R is 0.05 vs. 200 nM for CCK2R) .…”

“…A CCK1R‐selective agonist hexapeptide [Hpa‐Nle‐Gly‐Trp‐Lys(2‐tolylaminocarbonyl)‐Asp‐( N ‐methyl)Phe‐NH 2 ] referred to in previous reports as compound 7 , was synthesized internally using methods similar to those reported and is hereafter referred to as AC170222. AC170222 was reported to be 4000‐fold more selective for CCK1R versus CCK2R (Ki for CCK1R is 0.05 vs. 200 nM for CCK2R) . A peptidic CCK2R‐selective agonist [Boc‐Trp‐( N ‐methyl)Nle‐Asp‐Phe‐NH 2 ] was synthesized using previously reported methods and is hereafter referred to as AC170236.…”

Role of cholecystokinin in appetite control and body weight regulation

“…It has been reasoned that the development of biologically stable CCK 1 receptor agonists, which can be administered orally, may provide a means of inhibiting food intake and reducing body weight. There are two main classes, the tetra‐ and hexapeptides and the 1,5‐benzodiazepine CCK 1 receptor agonists, which, like CCK, have been shown to inhibit energy intake in rat models when administered acutely (87–91). In the only report relating to the effects of a CCK 1 receptor agonist, GW181771, in humans, there was a dose‐dependent decrease in energy intake over 24 h in obese women (http://www.gsk.com/press_archive).…”