POTENT ANTAGONISTS OF SOMATOSTATIN - SYNTHESIS AND BIOLOGY

The search for synthetic analogues of somatostatin (SRIF) which exhibi t selective affinities for the five known receptor subtypes (sst(1-5)) has generated a large number of potent agonist analogues. Many of the se agonists display good subtype selectivities and affinities for the subtypes 2, 3, and 5, with very few selective for sst(1) or sst(4). Un til the recent report by Bass and co-workers (Mel. Pharmacol. 1996, 50 , 709-715; erratum, Mol. Pharmacol. 1997, 51, 170), no true antagonist s had been discovered, let alone any displaying differential receptor subtype selectivity. In this present study, we explore the effect of t his putative L-5,D-6 antagonist motif on various series of somatostati n agonist analogues, both linear and cyclic. It was found that many D- 5,L-6 agonists could be converted into competitive antagonists by appl ying this motif, the most potent of which was H-Nal-cyclo[DCys-Pal-DTr p-Lys-Val-Cys]-Nal-NH2 (32). This antagonist was selective for hsst(2) 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 ant agonists should provide valuable tools for characterizing the many imp ortant physiological functions of this neuropeptide.