A Backbone-Cyclic, Receptor 5-Selective Somatostatin Analogue:  Synthesis, Bioactivity, and Nuclear Magnetic Resonance Conformational Analysis

Cyclo(PheN2-Tyr-d-Trp-Lys-Val-PheC3)-Thr-NH2 (PTR 3046), a backbone-cyclic somatostatin analogue, was synthesized by solid-phase methodology. The binding characteristics of PTR 3046 to the different somatostatin receptors, expressed in CHO cells, indicate high selectivity to the SSTR5 receptor. PTR...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1998-03, Vol.41 (6), p.919-929
Main Authors: Gilon, Chaim, Huenges, Martin, Mathä, Barbara, Gellerman, Gary, Hornik, Vered, Afargan, Michel, Amitay, Oved, Ziv, Ofer, Feller, Etty, Gamliel, Asher, Shohat, Dvira, Wanger, Mazal, Arad, Oded, Kessler, Horst
Format: Article
Language:English
Subjects:
Amylases - secretion
Animals
Biological and medical sciences
Blood Proteins - metabolism
Bombesin - pharmacology
Ceruletide - pharmacology
CHO Cells
Cricetinae
Enzyme-Linked Immunosorbent Assay
Glucagon - blood
Growth Hormone - blood
Hormones. Endocrine system
Humans
Kidney - metabolism
Lipase - secretion
Magnetic Resonance Spectroscopy
Male
Medical sciences
Pancreas - drug effects
Pancreas - secretion
Peptides, Cyclic - chemical synthesis
Peptides, Cyclic - chemistry
Peptides, Cyclic - metabolism
Peptides, Cyclic - pharmacokinetics
Pharmacology. Drug treatments
Pituitary Gland - drug effects
Pituitary Gland - metabolism
Protein Conformation
Rats
Rats, Wistar
Receptors, Somatostatin - biosynthesis
Receptors, Somatostatin - metabolism
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Summary:Cyclo(PheN2-Tyr-d-Trp-Lys-Val-PheC3)-Thr-NH2 (PTR 3046), a backbone-cyclic somatostatin analogue, was synthesized by solid-phase methodology. The binding characteristics of PTR 3046 to the different somatostatin receptors, expressed in CHO cells, indicate high selectivity to the SSTR5 receptor. PTR 3046 is highly stable against enzymatic degradation as determined in vitro by incubation with rat renal homogenate and human serum. The biological activity of PTR 3046 in vivo was determined in rats. PTR 3046 inhibits bombesin- and caerulein-induced amylase and lipase release from the pancreas without inhibiting growth hormone or glucagon release. The major conformation of PTR 3046 in CD3OH, as determined by NMR, is defined by a type II‘ β-turn at d-Trp-Lys and a cis amide bond at Val-PheC3.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm970633x