Potent antagonists of somatostatin: synthesis and biology

Journal of Medicinal Chemistry
S J HocartDavid H Coy

Abstract

The search for synthetic analogues of somatostatin (SRIF) which exhibit selective affinities for the five known receptor subtypes (sst1-5) has generated a large number of potent agonist analogues. Many of these agonists display good subtype selectivities and affinities for the subtypes 2, 3, and 5, with very few selective for sst1 or sst4. Until the recent report by Bass and co-workers (Mol. Pharmacol. 1996, 50, 709-715; erratum, Mol. Pharmacol. 1997, 51, 170), no true antagonists had been discovered, let alone any displaying differential receptor subtype selectivity. In this present study, we explore the effect of this putative L5,D6 antagonist motif on various series of somatostatin agonist analogues, both linear and cyclic. It was found that many D5,L6 agonists could be converted into competitive antagonists by applying this motif, the most potent of which was H-Nal-cyclo[DCys-Pal-DTrp-Lys-Val-Cys]-Nal-NH2 (32). This antagonist was selective for hsst2 with an affinity of 75 nM and an IC50 of 15.1 nM against SRIF-14 in a rat in vitro antagonist bioassay. Receptor-selective somatostatin antagonists should provide valuable tools for characterizing the many important physiological functions of this neuropeptide.

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Citations

Apr 12, 2003·European Journal of Pharmacology·Caroline NunnDaniel Hoyer
May 17, 2001·Bioorganic & Medicinal Chemistry Letters·S NarayananR Jain
Apr 9, 2009·Journal of Medicinal Chemistry·Judit ErchegyiJean Claude Reubi
Mar 11, 2000·British Journal of Pharmacology·C PetrucciP Bagnoli
Feb 24, 2001·Chemical & Pharmaceutical Bulletin·M HaramuraE Murayama
Oct 21, 2006·Chemistry & Biology·Mihaela GinjHelmut R Maecke
Aug 29, 2003·Journal of Enzyme Inhibition and Medicinal Chemistry·Patricia LabarrèreHubert Vaudry
Sep 5, 2001·The Journal of Peptide Research : Official Journal of the American Peptide Society·A JaneckaT Janecki
May 22, 2019·Journal of Labelled Compounds & Radiopharmaceuticals·Rosalba Mansi, Melpomeni Fani
Oct 10, 2001·Bioorganic & Medicinal Chemistry Letters·B A HayT W Siegel
Dec 12, 2003·Journal of Medicinal Chemistry·Jean RivierJean Claude Reubi
Aug 25, 2001·Journal of Medicinal Chemistry·L PoitoutC Thurieau
Sep 26, 2003·Biochimica Et Biophysica Acta·Lars Neisig MøllerJens Juul Holst
Apr 21, 2001·Journal of Medicinal Chemistry·W G RajeswaranD H Coy
Jan 25, 2002·Journal of Medicinal Chemistry·Masayuki HaramuraEigoro Murayama
Mar 3, 1999·Journal of Medicinal Chemistry·L CerviniJ Rivier
Jun 4, 1999·Journal of Medicinal Chemistry·S J HocartD H Coy

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