Structure activity of C‐terminal modified analogs of Ac‐CCK‐7

Abstract

Previous work indicates that both the C‐terminal phenylalanine amide and the tryptophan moieties of chole‐cystokinin (CCK) are critical pharmacophores for interaction with either the A or B receptor subtypes. We have examined a series of analogs of Ac‐CCK‐7 [Ac‐Tyr(SO3H)‐Met‐Gly‐Trp‐Met‐Asp‐Phe33‐NH2] (2) in which the phenyl ring of the C‐terminal Phe‐NH2 has been modified. Compounds were assessed in binding assays using homogenated rat pancreatic membranes and bovine striatum as the source of CCK‐A and CCK‐B receptors respectively and for anorectic activity after intraperitoneal administration to rats. Substitution of a number of cycloalkyi or bicyclic aryl moieties for the phenyl ring of phenylalanine33 including cyclopentyl (20), cyclohexyl (21), cyclooctyl (23), 2‐(5,6,7,8‐tetrahydro)naphthyl (26), 2‐naphthyl (27), and 1‐naphthyl (29) led to analogs with 10–70 times the anorectic potency of 2. The anorectic activity of 21 was blocked by the specific CCK‐A receptor antagonist MK‐329. Other bulky aliphatic groups in place of the phenylalanine33 aromatic ring such as isopropyl, 2‐adamantyl and cyclohexylmethyl gave derivatives similar to 2 in potency. While most of the new compounds were comparable to CCK in binding assays, 23, 26, 27 and 29 were exceptionally potent with IC50s 10‐11‐10‐14 M in the pancreas. Compounds 23 and 29 were further evaluated for their ability to stimulate amylase secretion and found to have potencies similar to that of CCK. The dissociation between potency in the binding and amylase secretion assays suggests that they may interact with a high affinity binding site which is not coupled to amylase secretion. We conclude that CCK receptors possess a generous hydrophobic pocket capable of accommodating large alkyl groups in place of the side chain of phenylalanine33 and that the pharmacological profile of CCK analogs can be tailored by appropriate exploitation of this finding.

Structure–Activity Relationships and Characterization of Highly Selective, Long-Acting, Peptide-Based Cholecystokinin 1 Receptor Agonists

“…Replacement of 33-Phe with N -methyl-Phe (MePhe) was reported to slightly increase CCK-1R selectivity by lowering CCK-2R affinity and to enhance CCK-1R affinity and selectivity when combined with DAsp in position 32 . Position 33 seems to tolerate a range of aromatic amino acid substitutions including 1Nal, − whereas diverging results were published for analogues with cyclohexylalanine in position 33. − However, most of these conclusions are based on very different reported experiments performed 20–30 years ago with partly inconsistent results. A systematic reinvestigation of the CCK peptide sequence to optimize CCK-1R potency and selectivity seemed therefore necessary and is an essential part of the work described here.…”