Minor Structural Differences in Boc-CCK-4 Derivatives Dictate Affinity and Selectivity for CCK-A and CCK-B Receptors

• Published in: Journal of medicinal chemistry Vol. 40; no. 7; pp. 1169 - 1172
• Main Authors: Shiosaki, Kazumi, Lin, Chun Wel, Kopecka, Hana, Bianchi, Bruce, Miller, Thomas, Stashko, Michael, Witte, David
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 28.03.1997; Amer Chemical Soc
• Subjects: Biological and medical sciences; Cell Line; Chemistry, Medicinal; Life Sciences & Biomedicine; Magnetic Resonance Spectroscopy; Mass Spectrometry; Medical sciences; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Receptor, Cholecystokinin A; Receptor, Cholecystokinin B; Receptors, Cholecystokinin - metabolism; Science & Technology; Structure-Activity Relationship; Tetragastrin - analogs & derivatives; Tetragastrin - chemistry; Tetragastrin - metabolism; CHOLECYSTOKININ TETRAPEPTIDE 30-33; POTENT; HUMAN BRAIN; ANALOGS; CLONING; FUNCTIONAL EXPRESSION; RELEASE; ANTAGONISTS; AGONISTS; FAMILY; Peptides; Rodentia; Central nervous system; Benzene derivatives; Selectivity; In vitro; Vertebrata; Biological fixation; Chemical modification; Mammalia; Guinea pig; Structure activity relation; Tetrapeptide; Animal; Peptidergic receptor; Affinity; Ureas; Cholecystokinin; Pancreas; Chemical synthesis; Brain (vertebrata)
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm960509y

We previously reported novel Boc-CCK-4 (Boc-Trp-Met-Asp-Phe-NH2) derivatives possessing the general structure Boc-Trp-Lys[Nε-CO-NH-(R-Ph)]-Asp-Phe-NH2 (Shiosaki et al. J. Med. Chem. 1991, 34, 2837−2842). In contrast to Boc-CCK-4, which is 70-fold selective for the CCK-B receptor, the modified lysine-bearing tetrapeptides were highly potent and selective full agonists at the CCK-A receptor. Further investigation of the structure−activity profile following modification of the substituted phenylurea moiety appended off the lysine revealed that moving certain substituents, e.g. nitro or acetyl, from the 2- or 3-position on the phenyl ring to the 4-position, a relatively minor and subtle structural modification within the tetrapeptide, resulted in loss of CCK-A receptor selectivity and development of a trend toward CCK-B selectivity. These tetrapeptides, e.g. Boc-Trp-Lys[Nε-CO-NH-(4-NO2-Ph)]-Asp-Phe-NH2 and Boc-Trp-Lys[Nε-CO-NH-(4-Ac-Ph)]-Asp-Phe-NH2, were full agonists relative to CCK-8 in stimulating intracellular calcium mobilization in a cell line that expresses the CCK-B receptor.