Identification of Potent Non-Peptide Somatostatin Antagonists with sst₃ Selectivity

Abstract

Using a solution-phase parallel synthesis strategy, a series of non-peptide somatostatin analogues were prepared, and their binding affinities to the five human somatostatin receptor subtypes (sst(1-5)) were determined. Imidazolyl derivatives 2 were found to bind with moderate affinity but with high selectivity to the sst(3) receptor subtype. Further modifications of these structures led to a more potent class of ligands, the tetrahydro-beta-carboline derivatives 4. Among these, compounds 4k (BN81644) and 4n (BN81674) bind selectively and with high affinity to the sst(3) receptor subtype (K(i) = 0.64 and 0.92 nM, respectively). Furthermore, 4k and 4n reverse the inhibition of cyclic AMP accumulation induced by 1 nM somatostatin via sst(3) receptors, with IC(50) = 2.7 and 0.84 nM, respectively. The most potent compound 4n was shown to be a competitive antagonist of human sst(3) receptors by increasing the EC(50) of SRIF-14-mediated inhibition of cAMP accumulation with a K(B) of 2.8 nM (where K(B) is the concentration of antagonist that shifts the agonist dose-response 2-fold). These new derivatives are, to our knowledge, the first potent and highly selective non-peptide human sst(3) antagonists known and, as such, are useful tools for investigating the physiological role of sst(3) receptors.

Somatostatin and Somatostatin Receptors

“…In a unique design, open-chain octapeptide antagonists BIM 23056, BIM 23627, and BIM 23454 were selected for their preferentially binding to SSTR5 and SSTR2 respectively; however, both compounds do show partial affinities for the other subtypes to various degrees (Shimon et al 1997b;Tulipano et al 2002). The first high-affinity nonpeptide antagonist was designed for SSTR3 with greater than 1000-fold selectivity (Poitout et al 2001). An SSTR1 nonpeptide antagonist SRA880, was recently characterized in vitro to have modest selectivity of up to 100-fold (Hoyer et al 2004 …”

New approaches to therapy of cancers of the stomach, colon and pancreas based on peptide analogs

“…[33]. In addition, several peptidic and nonpeptidic selective ligands for sst [1][2][3][4][5] are being developed [34,35].…”

Prolactin and Angiogenesis: Biological Implications of Microheterogeneity

“…Because of this, the C-terminal 16K fragment of hPRL may not have antiangiogenic action. Three residues, Phe7-Trp8-Lys9, in SST sequence appear to have the crucial role in binding with high affinity to all SST receptors, SSTR1 to SSTR5 (Poitout et al 2001). However, in the synthetic sequence derived from buPRL, Ala1-Gln2-Gly3-Lys4-Gly5-Phe6-Ile7-Thr8-Met9-Ala10-Leu11-Asn12-Ser13-Cys14, 'Ile7-Thr8-Met9' is found instead of 'Phe7-Trp8-Lys9'.…”