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.
MeSH terms
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Adamantane / analogs & derivatives
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Adamantane / chemistry
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Adamantane / metabolism
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Amino Acid Sequence
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Animals
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Appetite Depressants / chemistry
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Appetite Depressants / metabolism
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Appetite Depressants / pharmacology
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CHO Cells
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Cricetinae
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Humans
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Indoles / chemistry
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Indoles / metabolism
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Ligands
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Magnetic Resonance Spectroscopy
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Male
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Meglumine / analogs & derivatives
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Meglumine / chemistry
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Meglumine / metabolism
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Molecular Sequence Data
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Peptoids
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Rats
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Receptor, Cholecystokinin A
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Receptor, Cholecystokinin B
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Receptors, Cholecystokinin / metabolism*
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Spectrometry, Mass, Fast Atom Bombardment
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Tetragastrin / analogs & derivatives*
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Tetragastrin / chemistry
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Tetragastrin / metabolism
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Tetragastrin / pharmacology
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Tryptophan / analogs & derivatives
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Tryptophan / chemistry
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Tryptophan / metabolism
Substances
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Appetite Depressants
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Indoles
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Ligands
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PD 135118
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Peptoids
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Receptor, Cholecystokinin A
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Receptor, Cholecystokinin B
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Receptors, Cholecystokinin
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Tetragastrin
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PD 134308
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A 71623
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Meglumine
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Tryptophan
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Adamantane