title: Identification of potent non-peptide somatostatin antagonists with sst(3) 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.
authors.affiliation: Institut Henri Beaufour, 5 Avenue du Canada, F-91966 Les Ulis, France. lydie.poitout@beaufour-ipsen.com
authors.forename: L
authors.initials: L
authors.lastname: Poitout
authors.forename: P
authors.initials: P
authors.lastname: Roubert
authors.forename: M O
authors.initials: MO
authors.lastname: Contour-Galcéra
authors.forename: C
authors.initials: C
authors.lastname: Moinet
authors.forename: J
authors.initials: J
authors.lastname: Lannoy
authors.forename: J
authors.initials: J
authors.lastname: Pommier
authors.forename: P
authors.initials: P
authors.lastname: Plas
authors.forename: D
authors.initials: D
authors.lastname: Bigg
authors.forename: C
authors.initials: C
authors.lastname: Thurieau
mesh_terms: D000818:Animals; D016466:CHO Cells; D002243:Carbolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D006224:Cricetinae; D000242:Cyclic AMP / Q000096:biosynthesis; D006801:Humans; D008024:Ligands; D011869:Radioligand Assay; D017481:Receptors, Somatostatin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013004:Somatostatin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: C435197:BN 81674; D002243:Carbolines; D008024:Ligands; D017481:Receptors, Somatostatin; C101130:somatostatin receptor type 1; D013004:Somatostatin; D000242:Cyclic AMP