Novel sst(4)-selective somatostatin (SRIF) agonists. 2. Analogues with beta-methyl-3-(2-naphthyl)alanine substitutions at position 8.
J Med Chem
; 46(26): 5587-96, 2003 Dec 18.
Article
em En
| MEDLINE
| ID: mdl-14667213
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).
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Base de dados:
MEDLINE
Assunto principal:
Oligopeptídeos
/
Peptídeos Cíclicos
/
Somatostatina
/
Receptores de Somatostatina
/
Alanina
/
Naftalenos
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Humans
Idioma:
En
Ano de publicação:
2003
Tipo de documento:
Article