title: Modification of receptor selectivity and functional activity in cholecystokinin peptoid ligands.
abstract: Hybrid analogs of the cholecystokinin A (CCK-A) receptor selective tetrapeptide agonist Boc-Trp-Lys(Tac)-Asp-MePhe-NH2 (1,A-71623) and the CCK-B receptor selective antagonists PD-135118 (2) and CI-988 (3) were prepared. Incorporation of the Lys(Tac) side chain into 2 produced a moderately potent antagonist of CCK-8 in the isolated guinea pig gallbladder (GPGB). Incorporation of the Lys(Tac) side chain into 3 produced the novel agonist analog 7 (EC50 = 28 nM in the GPGB) with excellent affinity for both human CCK-A (IC50 = 12 nM) and CCK-B (IC50 = 17 nM) receptors. Analog 7 was a full agonist (EC50 = 3.5 nM) for calcium mobilization on CHO-K1 cells expressing hCCK-A receptors but a partial agonist on CHO-K1 cells expressing hCCK-B receptors, eliciting a weak agonist response (EC50 = 2800 nM) and antagonizing CCK-8-induced calcium mobilization (KB = 20 nM). Despite this unusual in vitro profile, analog 7 was a potent anorectic agent in rats (ED50 = 30 nmol/kg) following intraperitoneal administration.
authors.affiliation: Department of Medicinal Chemistry, Glaxo Research Institute, Research Triangle Park, North Carolina 27709, USA.
authors.forename: M
authors.initials: M
authors.lastname: Dezube
authors.forename: E E
authors.initials: EE
authors.lastname: Sugg
authors.forename: L S
authors.initials: LS
authors.lastname: Birkemo
authors.forename: D K
authors.initials: DK
authors.lastname: Croom
authors.forename: R W
authors.initials: RW
authors.lastname: Dougherty
authors.forename: G N
authors.initials: GN
authors.lastname: Ervin
authors.forename: M K
authors.initials: MK
authors.lastname: Grizzle
authors.forename: M K
authors.initials: MK
authors.lastname: James
authors.forename: M F
authors.initials: MF
authors.lastname: Johnson
authors.forename: J T
authors.initials: JT
authors.lastname: Mosher
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001067:Appetite Depressants / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D016466:CHO Cells; D006224:Cricetinae; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000378:metabolism; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008536:Meglumine / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D008969:Molecular Sequence Data; D034444:Peptoids; D051381:Rats; D043886:Receptor, Cholecystokinin A; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin / Q000378:metabolism*; D016339:Spectrometry, Mass, Fast Atom Bombardment; D013758:Tetragastrin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D014364:Tryptophan / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism
chemical_list: D001067:Appetite Depressants; D007211:Indoles; D008024:Ligands; C095358:PD 135118; D034444:Peptoids; D043886:Receptor, Cholecystokinin A; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin; D013758:Tetragastrin; C065599:PD 134308; C066278:A 71623; D008536:Meglumine; D014364:Tryptophan; D000218:Adamantane