Comparison of CCK-8 receptors in the pancreas and brain of rats using CCK-8 analogues.

Takeda, Yasuo; Hoshino, Minoru; Yanaihara, Noboru; Yanaihara, Chizuko; Isobe, Junko; Sugiura, Nobuo; Kashimoto, Kazuhisa; Takáno, Yukio; Kamiya, Hiro-o

doi:10.1254/jjp.49.471

Cited by 8 publications

(4 citation statements)

References 27 publications

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“…For our first modification, the N-terminal Asp of SNF-9007 was removed, since it is known that the free N-terminal tyrosine is essential for high potency of peptidic ligands at opioid receptors (Table ). It is known that Asp 0 can be removed without greatly affecting binding affinity and potency at CCK receptors, particularly at the CCK-2 receptors where CCK-4 (C-terminal tetrapeptide) remains potent . To explore the optimal binding at opioid receptors, as well as CCK receptors, a variety of amino acids were substituted at position 2 (analogues 1 − 6 , Table ).…”

Section: Resultsmentioning

confidence: 99%

Structure−Activity Relationships of Bifunctional Peptides Based on Overlapping Pharmacophores at Opioid and Cholecystokinin Receptors

et al. 2006

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Cholecystokinin (CCK) has been identified as a pronociceptive endogenous peptide which also possesses antiopioid actions. CCK may be upregulated in conditions of chronic pain or during sustained morphine administration resulting in attenuation of opioid-mediated pain relief. These complex interactions between opioids and endogenous CCK receptor systems have suggested the need for a new paradigm in drug design for some states of chronic pain. In these circumstances the rational design of potential drugs for the treatment of these conditions must be based on one ligand for multiple targets. We have designed a single peptide which can interact with δ and μ opioid receptors as agonists and with CCK receptors as antagonists. The ligands were designed based on a model of overlapping pharmacophores of opioid and CCK peptide ligands, which incorporates opioid pharmacophores at the N-terminal and CCK tetrapeptide pharmacophores at the C-terminal of the designed ligands. We measured binding and activities of our bifunctional peptides at opioid and CCK receptors. Compound 11 (Tyr-D-Ala-Gly-D-Trp-NMeNle-Asp-Phe-NH 2 ) demonstrated opioid agonist properties at δ and μ receptors (IC 50 = 63 ± 27 nM and 150 ± 65 nM, respectively in MVD and GPI tissue assays) and high binding affinity at CCK-1 and CCK-2 receptors (K i = 320 and 1.5 nM, respectively). Compound 9 (Tyr-D-Nle-Gly-Trp-Nle-Asp-Phe-NH 2 ) displayed potent agonist activity at δ and μ receptors (IC 50 = 23 ±10 nM and 210 ± 52 nM, respectively in MVD and GPI tissue assays), with a balanced binding affinity for CCK-1 and CCK-2 receptors (K i = 9.6 and 15 nM, respectively). These results provide evidence supporting the concept that opioid and CCK receptors have overlapping pharmacophores required for binding affinity and biological activity and that designing overlapping pharmacophores of two peptides into a single peptide is a valid drug design approach.

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Section: Resultsmentioning

confidence: 99%

Structure−Activity Relationships of Bifunctional Peptides Based on Overlapping Pharmacophores at Opioid and Cholecystokinin Receptors

et al. 2006

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“…Substitutions of 28-Met with non-natural norleucine (Nle), Leu, and Pro, but not DNle, were well-tolerated by CCK-1R . Almost any reported replacement of 29-Gly resulted in major loss of CCK-1R affinity or potency, − with the exception of one example with N -methylglycine (sarcosine) , and one with the fluorescent artificial amino acid Aladan . Even minor changes of the 30-Trp residue were not tolerated well by CCK-1R, unless 30-Trp was replaced with 2-naphthylalanine or certain monofluorinated Trp derivatives .…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2019

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A group of peptide-based, long-acting, stable, highly selective cholecystokinin 1 receptor (CCK-1R) agonists with the potential to treat obesity has been identified and characterized, based on systematic investigation of synthetic CCK-8 analogues with N-terminal linkage to fatty acids. Sulfated Tyr in such compounds was stable in neutral buffer. CCK-1R selectivity was achieved mostly by introducing d-N-methyl-Asp instead of Asp at the penultimate position of CCK-8. Our compound 9 (NN9056) showed similar in vitro CCK-1R potency and CCK-1R affinity as CCK-8, very high selectivity for CCK-1R over the cholecystokinin 2 receptor (CCK-2R), strong reduction of food intake in lean pigs for up to 48 h after one subcutaneous injection without adverse effects, a plasma half-life of 113 h in minipigs after intravenous injection, and acceptable chemical stability in a neutral liquid formulation. In addition, we found a highly selective CCK-2R agonist by replacing Gly in a CCK-8 derivative with Glu.

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“…Both of them have been extensively studied, particularly in relation to food intake regulation, and have brought a great deal of confusion when it came to anxiety and panic. They have differential affinity for CCK receptors [11,12] different distribution in both the periphery and the brain [13,14] and have various effects on behavior.…”

Section: Introductionmentioning

confidence: 99%

Breaking into Merck's CCK Patents: the Starting Point of PNB Vesper Life Science to Design and Develop Cholecystokinin(CCK)-Antagonists as Targeted Chemotherapeutics

Lattmann¹

2018

DDIPIJ

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Early anti-cancer research was dominated by the development of alkylating agents, followed by the discovery of a variety of anti-metabolites, which were useful anti-viral agents at the same time. Current anti-cancer drugs are designed towards molecular targets in order to reduce their toxicity and to enhance the selectivity on the cancer cells. Within an increasingly growing number of molecular targets, the cholecystokinin, as a neuro modulator, became an important anti-cancer target, especially when it was shown that cholecystokinin regulates the invasiveness of human pancreatic cancer cell lines via the protein kinase C pathway. The low potency and the lack of subtype receptor selectivity of those early non-peptide CCK-antagonists, was improved in the following generations of CCK antagonists. These potent and selective antagonists have shown disappointing results in clinical trials due to a poor bioavailability. Initially cholecystokinin was discussed as growth factor, not only in pancreatic cancer, but also for lung, breast, colon and brain cancer, followed by a detailed discussion of over 20 different chemical classes having been developed to date, mainly for the area of neuroscience. Loxiglumide, CI-988, Devazepide, L-365,260 and YM022 are highlighted including in vivo studies and clinical trials. Moreover, CCK antagonists were found useful in the enhancement of the analgesic effects of morphine and the anti-neo plastic effect of cis-platinium. Clinical trials are ongoing. It is concluded that non peptidal cholecystokinin receptor antagonists are modern, non-toxic anti-cancer agents.

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Comparison of CCK-8 receptors in the pancreas and brain of rats using CCK-8 analogues.

Cited by 8 publications

References 27 publications

Structure−Activity Relationships of Bifunctional Peptides Based on Overlapping Pharmacophores at Opioid and Cholecystokinin Receptors

Structure−Activity Relationships of Bifunctional Peptides Based on Overlapping Pharmacophores at Opioid and Cholecystokinin Receptors

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

Breaking into Merck's CCK Patents: the Starting Point of PNB Vesper Life Science to Design and Develop Cholecystokinin(CCK)-Antagonists as Targeted Chemotherapeutics

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