PMID: 11931620Apr 5, 2002Paper

Human somatostatin receptor specificity of backbone-cyclic analogues containing novel sulfur building units

Journal of Medicinal Chemistry
Sharon GazalChaim Gilon

Abstract

Somatostatin-14 (somatostatin) and its clinically available analogues octreotide, lanreotide, and vapreotide are potent inhibitors of growth hormone, insulin, and glucagon release. Recently, a novel backbone cyclic somatostatin analogue c(GABA-Phe-Trp-(D)Trp-Lys-Thr-Phe-GlyC3-NH(2)) (analogue 1, PTR 3173) that possesses in vivo endocrine selectivity was described. This long-acting octapeptide exhibits high affinity to human recombinant somatostatin receptors (hsst) hsst2, hsst4, and hsst5. Its novel binding profile resulted in potent in vivo inhibition of growth hormone but not of insulin release. We report the synthesis, bioactivity, and structure-activity relationship studies of compounds related to 1. In these analogues, the lactam bridge of 1 was replaced by a backbone disulfide bridge. We present a novel approach for conformational constraint of peptides by utilizing sulfur-containing building units for on-resin backbone cyclization. These disulfide backbone cyclic analogues of 1 showed significant metabolic stability as tested in various enzyme mixtures. Receptor binding assays revealed different receptor selectivity profiles for these analogues in comparison to their prototype. It was found that analogues of 1, bearing a...Continue Reading

References

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Citations

Jun 10, 2011·Journal of Medicinal Chemistry·Yftah Tal-GanChaim Gilon
Jul 2, 2003·Amino Acids·Y L Janin
Jul 1, 2010·Expert Opinion on Drug Discovery·Oded OvadiaHorst Kessler
Jul 23, 2013·Frontiers in Neuroendocrinology·Marily Theodoropoulou, Günter K Stalla
May 12, 2005·The Journal of Peptide Research : Official Journal of the American Peptide Society·J SpenglerF Albericio
Sep 3, 2013·Expert Opinion on Therapeutic Targets·Marije J VeenstraLeo J Hofland
Aug 20, 2010·Biochimica Et Biophysica Acta·Aviad LevinMichael Bukrinsky
Dec 5, 2003·Nature Reviews. Drug Discovery·Gisbert WeckbeckerChristian Bruns
Mar 3, 2010·Journal of Peptide Science : an Official Publication of the European Peptide Society·Mattan HurevichChaim Gilon
Jun 23, 2015·Biopolymers·Ana I Fernández-LlamazaresFernando Albericio
May 26, 2017·Biomedicines·Yosi GiladGary Gellerman
Jan 25, 2011·Chembiochem : a European Journal of Chemical Biology·Rosario RamónAntoni Riera
Sep 13, 2017·Amino Acids·Maria C RodriguezPredrag Cudic
Feb 5, 2021·Journal of Clinical Medicine·Maria Celeste CantoneGiovanni Vitale
Jan 24, 2008·Journal of Medicinal Chemistry·Debora D'AddonaMauro Ginanneschi
May 17, 2008·Molecular Pharmaceutics·Weiqiang Cheng, Lee-Yong Lim

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