PMID: 11312929Apr 21, 2001Paper

Highly potent and subtype selective ligands derived by N-methyl scan of a somatostatin antagonist

Journal of Medicinal Chemistry
W G RajeswaranDavid H Coy

Abstract

The search for synthetic peptide analogues of somatostatin (SRIF) which exhibit selective affinities for the five known receptor subtypes (sst1-5) has generated a large number of potent agonists. Some of these agonists display good subtype selectivities and affinities for the subtypes 1, 2, 3, and 5, including analogues created by N-methyl amino acid substitutions in a standard octapeptide analogue format. We have now extended this peptide backbone N-methylation approach to a potent somatostatin receptor antagonist series using the antagonist Cpa-cyclo(DCys-Pal-DTrp-Lys-Thr-Cys)-Nal-NH2 9 reported from this laboratory as the lead structure. Synthetic analogues were tested for their ability to inhibit somatostatin-stimulated GH release from rat pituitary cells in culture and to displace 125I-labeled somatostatin from CHO cells transfected with the five known human somatostatin receptors. Several interesting observations resulted from the study. N-Methylation at the Lys(9) residue (5) increased the rat GH release inhibitory potency nearly 4-fold to 0.73 nM but resulted in little change in the binding affinity for human type 2 receptor. This analogue also had a high affinity of 5.98 nM for sst5 receptor (compared to 1.4 nM for som...Continue Reading

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Citations

Feb 24, 2011·The Journal of Biological Chemistry·Madhumita Ghosh, Agnes Schonbrunn
Jan 24, 2009·The Journal of Biological Chemistry·Karen S HarrisMichael Foley
Jun 29, 2006·Pancreas·Nikiforos BallianXiao-Ping Wang
Feb 4, 2010·Journal of Peptide Science : an Official Publication of the European Peptide Society·Hortensia RodríguezFernando Albericio
Apr 30, 2015·Journal of Peptide Science : an Official Publication of the European Peptide Society·Antonella LeggioAngelo Liguori
Jan 24, 2003·Expert Opinion on Therapeutic Targets·Hong-Tao LuRichard Horuk
Apr 28, 2012·The American Journal of Pathology·Beatrice WaserJean Claude Reubi
Dec 15, 2007·Chemistry : a European Journal·Jayanta ChatterjeeHorst Kessler
Sep 29, 2005·Journal of Peptide Science : an Official Publication of the European Peptide Society·Eric BironHorst Kessler
Aug 16, 2003·Endocrine Reviews·Jean Claude Reubi
Apr 28, 2005·Molecular Pharmacology·Qisheng LiuAgnes Schonbrunn
Feb 23, 2011·Natural Product Reports·Charles R RobertsonGrzegorz Bulaj
Jan 1, 2016·Molecular Cancer Therapeutics·Yan WangKit S Lam
Feb 6, 2009·Journal of Medicinal Chemistry·Judit Tulla-PucheFernando Albericio
Jul 23, 2013·Journal of the American Chemical Society·Giuseppe CecereDavid W C MacMillan
May 24, 2019·The Journal of Organic Chemistry·Carlos J SaavedraAlicia Boto
Aug 12, 2017·Organic Letters·Zhengyin PanWu Su

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