Structural requirements for the satiety effect of CCK-8

Rosamond, James D.; Comstock, Jeanne M.; Thomas, Nancie J.; Clark, Anne M.; Blosser, James C.; Simmons, Roy D.; Gawlak, Daniel; Loss, Mary; Augello-Vaisey, Susan J.; Spatola, Arno F.; Benovitz, Deanne E.

doi:10.1007/978-94-010-9595-2_182

Cited by 5 publications

(6 citation statements)

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“…CCK4 and desulfated CCK-8, that already show moderate nanomolar affinity and modest selectivity for CCK-B receptors.18,19 Meanwhile, impressive progress has been made in the development of potent and selective antagonists at both receptor subtypes.10,20 In relation to our ongoing studies on CCK, and specifically as part of our program directed toward CCK analogues as anorectic agents, we undertook structure-activity studies on a series of sulfated CCK7 analogues. Our studies followed those of Rosamond et al,21 who had demonstrated (18) Hruby, V. J.; Fang, S.; Knapp, R.; Kazmierski, W.; Lui, G. K.;…”

supporting

confidence: 66%

“…H-Trp-Nle-Asp-Phe-NHj Trifluoroacetate (21). Compound 20 (5.0 g, 7.4 mmol) was treated with a solution comprised of CH2C12 (100 mL), TFA (100 mL), dimethyl phosphite (4 mL), and anisóle (5 mL).…”

Section: Methodsmentioning

confidence: 99%

“…Boc This acid (42 mg, 0.16 mmol) was coupled to tetrapeptide 21 (124 mg, 0.18 mmol) according to general procedure A, with the mixed anhydride formed in 1:1 CH2C12:THF, and using NEt3 as base during the coupling step. The product was isolated by concentration of the reaction mixture followed by addition of H20 and HOAc to precipitate a solid, which was collected by filtration, washed with H20, and dried in vacuo to afford 111 mg (85%) of the title compound: MS (FAB4-) m/e 841 ( + Na)+, 719 (M + H -Boc)+; NMR (300 MHz, DMSO-de, selected data) 1.38 (s, Boc), 3.05 (m, lactam C-5 protons); 3.67 (d, J =17 Hz, 1 H), 3.88 (d, J = 17 Hz, 1 ), 4.09 (dd, J = 9,18 Hz, 1 ), 4.21 (m, 1 H), 4.35 (m, 1 ), 4.51 (m, 1 H), 4.57 (m, 1 H) (a-protons).…”

Section: Methodsmentioning

confidence: 99%

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Synthesis and biological activity of CCK heptapeptide analogs. Effects of conformational constraints and standard modifications on receptor subtype selectivity, functional activity in vitro, and appetite suppression in vivo

Holladay

Bennett²,

Tufano³

et al. 1992

J. Med. Chem.

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A series of modifications of the CCK7 analogue (des-NH2)Tyr(SO3-)-Nle-Gly-Trp-Nle-Asp-Phe-NH2 was prepared and tested for binding to guinea pig CCK-A and CCK-B receptors and in CCK-A-mediated functional assays. Selected analogues also were tested for appetite suppressant activity in rats. Several conformationally restricted residues in the C-terminal tetrapeptide region, including delta Z-Phe33, (N-Me)Phe33, (N-Me)Asp32, (N-Me)Leu31, and 3PP31 (3PP = trans-3-n-propyl-L- proline) were found to be acceptable modifications at one or both receptor subtypes. The (N-Me)Asp32 and (N-Me)Leu31 modifications afforded potent and selective CCK-A and CCK-B ligands, respectively. SAR studies in the N-terminal acyldipeptide region examined structural requirements for the side chain at position 28, where Gly and Pro replacements were found to possess high affinity at both receptor subtypes. Other conformationally restrictive modifications were less active. All of the analogues that showed high affinity (less than 10 nM) for the CCK-A receptor also were full agonists in amylase release and most were full or nearly full agonists in the phosphoinositide (PI) turnover assay, the most notable exception being the delta Z-Phe33 analogue, which showed 69% of the maximal response in the PI assay. Potent activity in suppression of food intake in rats was found for selected analogues.

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supporting

confidence: 66%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Synthesis and biological activity of CCK heptapeptide analogs. Effects of conformational constraints and standard modifications on receptor subtype selectivity, functional activity in vitro, and appetite suppression in vivo

Holladay

Bennett²,

Tufano³

et al. 1992

J. Med. Chem.

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“…15 We have previously reported that inversion of the stereochemistry at Asp 7 of 2 produced the CCK-A selective agonist 3. 16 We report here further studies of CCK-A agonists leading to the identification of the highly potent CCK-A selective agonist AR-R 15849 (6). 17…”

Section: Introductionmentioning

confidence: 87%

“…Only a small number of compounds have been reported to be CCK-A selective agonists, most notably a series of tetrapeptides. − Structure−activity relationships of CCK-A agonists suggest that the anionic group of Asp 7 in CCK-8 is important for agonist activity . We have previously reported that inversion of the stereochemistry at Asp 7 of 2 produced the CCK-A selective agonist 3 . We report here further studies of CCK-A agonists leading to the identification of the highly potent CCK-A selective agonist AR-R 15849 ( 6 )…”

Section: Introductionmentioning

confidence: 89%

Synthesis and Biological Evaluation of Potent, Selective, Hexapeptide CCK-A Agonist Anorectic Agents

Me¹,

Jm²,

Rd³

et al. 1997

J. Med. Chem.

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Cholecystokinin (CCK) is a 33-amino acid peptide with multiple functions in both the central nervous system (via CCK-B receptors) and the periphery (via CCK-A receptors). CCK mediation of satiety via the A-receptor subtype suggest a role for CCK in the management of obesity. The carboxy terminal octapeptide (CCK-8) is fully active in this regard, but is lacking in receptor selectivity, metabolic stability, and oral bioavailability. Inversion of the chirality of Asp7 in conjunction with N-methylation of Phe8 produces compound 5 which exhibits high affinity and 2100-fold selectivity for CCK-A receptors. Compound 6 (Hpa(SO3H)-Nle-Gly-Trp-Nle-MeAsp-Phe-NH2), derived from moving the N-methyl group from Phe to Asp, decreased CCK-B affinity substantially without affecting CCK-A affinity, giving a compound with 6600-fold selectivity for CCK-A receptors. These compounds inhibit food intake with nanomolar potency following intraperitoneal administration in fasted rats. In addition to greater potency, compound 6 produces weight loss in rats when administered over nine consecutive days. Intranasal administration of 6 potently inhibits feeding in beagle dogs. Compound 6 produces potent anorectic activity via the CCK-A receptor system.

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CCK heptapeptide analogs: Effect of conformational restrictions and standard modifications on selectivity and activity at CCK-A and CCK-B receptors

Holladay¹,

Bennett²,

Tufano³

et al. 1992

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Structural requirements for the satiety effect of CCK-8

Cited by 5 publications

References 4 publications

Synthesis and biological activity of CCK heptapeptide analogs. Effects of conformational constraints and standard modifications on receptor subtype selectivity, functional activity in vitro, and appetite suppression in vivo

Synthesis and biological activity of CCK heptapeptide analogs. Effects of conformational constraints and standard modifications on receptor subtype selectivity, functional activity in vitro, and appetite suppression in vivo

Synthesis and Biological Evaluation of Potent, Selective, Hexapeptide CCK-A Agonist Anorectic Agents

CCK heptapeptide analogs: Effect of conformational restrictions and standard modifications on selectivity and activity at CCK-A and CCK-B receptors

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