title: Novel sst(4)-selective somatostatin (SRIF) agonists. 2. Analogues with beta-methyl-3-(2-naphthyl)alanine substitutions at position 8.
abstract: We present a family of human sst(4)-selective, high-affinity (IC(50) = 2-4 nM) cyclic somatostatin (SRIF) octapeptides. These peptides result from the substitution of dTrp(8) in H-c[Cys(3)-Phe(6)-Phe(7)-DTrp(8)-Lys(9)-Thr(10)-Phe(11)-Cys(14)]-OH (SRIF numbering) (ODT-8) by one of the four conformationally biased stereoisomers of beta-methyl-3-(2-naphthyl)alanine (beta-Me2Nal). Whereas H-c[Cys-Phe-Phe-DNal-Lys-Thr-Phe-Cys]-OH (ODN-8, 2) has high affinity and marginal selectivity for human sst(3) (Reubi et al., Proc. Natl. Acad. Sci. U.S.A. 2000, 97, 13973-13978), H-c[Cys-Phe-Tyr-D-threo-beta-Me2Nal-Lys-Thr-Phe-Cys]-OH (5) has high affinity for all sst's except for sst(1); H-c[Cys-Phe-Tyr-L-threo-beta-Me2Nal-Lys-Thr-Phe-Cys]-OH (6) has high affinity for sst(4) (IC(50) = 2.1 nM), with more than 50-fold selectivity toward the other receptors. Analogues 7 and 8, containing d- and l-erythro-beta-Me2Nal instead of the corresponding threo derivatives at position 8, are essentially inactive at all receptors. Substitution of Tyr(7) in 5 and 6 by Aph(7) resulted in 9 and 10 with similar affinity patterns overall yet lowered affinity. The substitution of DCys(3) for Cys(3) in 5 and 6 yielded H-c[DCys-Phe-Tyr-D-threo-beta-Me2Nal-Lys-Thr-Phe-Cys]-OH (11) and H-c[DCys-Phe-Tyr-L-threo-beta-Me2Nal-Lys-Thr-Phe-Cys]-OH (12), with biological profiles almost identical to those of their parents 5 and 6 (i.e., high affinity for sst(2-5) for 11 and high affinity and selectivity for sst(4) for 12). Analogue 12, with high sst(4) affinity combined with the highest sst(4) selectivity among all tested compounds, is an agonist in the cAMP accumulation assay (EC(50) = 1.29 nM). Cold monoiodination of 12 yielded 14, with loss of sst(4) selectivity and loss of high affinity (IC(50) = 21 nM). Introduction of Tyr(2) in 9 and 10 and substitution of Cys(3) by dCys(3), to yield 15 and 16 (IC(50) = 9.8 and 61 nM, respectively, for sst(4) and limited selectivity), failed to generate a high-affinity (125)iodinatable sst(4)-selective ligand. Substitution of Phe by Tyr at position 11 in H-c[DCys-Phe-Phe-L-threo-beta-Me2Nal-Lys-Thr-Phe-Cys]-OH yielded 18 (IC(50) = 11.8 nM at sst(4)), with limited sst(4) selectivity (30-fold or greater at the other receptors) yet only slightly improved affinity over that of 14. Cold monoiodination of 18 yielded 20 (IC(50) = 30 nM at sst(4) and high selectivity). Whereas we were able, in this study, to identify a new family of sst(4)-selective, high-affinity compounds, our additional goal, to identify highly potent and sst(4)-selective ligands amenable to (125)iodination, could not be achieved satisfactorily. On the other hand, some of the diastereomers identified in this study, such as 5, 11, 17, and 19, are very potent ligands at all receptors but sst(1).
authors.affiliation: The Clayton Foundation Laboratories for Peptide Biology, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Judit
authors.initials: J
authors.lastname: Erchegyi
authors.forename: Botond
authors.initials: B
authors.lastname: Penke
authors.forename: Lajos
authors.initials: L
authors.lastname: Simon
authors.forename: Scott
authors.initials: S
authors.lastname: Michaelson
authors.forename: Sandra
authors.initials: S
authors.lastname: Wenger
authors.forename: Beatrice
authors.initials: B
authors.lastname: Waser
authors.forename: Renzo
authors.initials: R
authors.lastname: Cescato
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Schaer
authors.forename: Jean Claude
authors.initials: JC
authors.lastname: Reubi
authors.forename: Jean
authors.initials: J
authors.lastname: Rivier
mesh_terms: D000409:Alanine / Q000031:analogs & derivatives / Q000737:chemistry*; D000818:Animals; D001345:Autoradiography; D001667:Binding, Competitive; D002460:Cell Line; D006224:Cricetinae; D000242:Cyclic AMP / Q000096:biosynthesis; D006801:Humans; D007457:Iodine Radioisotopes; D007553:Isotope Labeling; D008024:Ligands; D008565:Membrane Proteins; D009281:Naphthalenes / Q000737:chemistry*; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011487:Protein Conformation; D011869:Radioligand Assay; D017481:Receptors, Somatostatin / Q000819:agonists* / Q000737:chemistry*; D013004:Somatostatin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D007457:Iodine Radioisotopes; D008024:Ligands; D008565:Membrane Proteins; D009281:Naphthalenes; D009842:Oligopeptides; D010456:Peptides, Cyclic; D017481:Receptors, Somatostatin; C480607:beta-methyl-3-(2-naphthyl)alanine; C480606:cyclo(cysteinyl-phenylalanyl-phenylalanyl-2-naphthylalanyl-lysyl-threonyl-phenylalanyl-cysteinyl); C098681:somatostatin receptor subtype-4; D013004:Somatostatin; D000242:Cyclic AMP; D000409:Alanine