Journal of Medicinal Chemistry
ARTICLE
a chelator is unexpected and is, at the moment, hard to explain
and understand from a structural point of view. In general, the
conversion of a peptide agonist to a peptide antagonist has
indeed been an empirical tour de force involving such modifica-
tions as deletions or the introduction of unnatural amino acids
with different chirality.43
In conclusion, the data presented here add an additional
degree of complexity when it comes to any attempt at rationaliz-
ing the governing parameters that will direct a particular biolo-
gical active peptide analogue to be selective or not, agonist or not,
antagonist or not, long acting or not, and probably, safe or not.
agonists of the somatostatin receptor through combinatorial chemistry.
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’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures and
b
additional references. This material is available free of charge via
’ AUTHOR INFORMATION
Corresponding Author
*Phone: (858) 453-4100, extension 1350. Fax: (858) 552-1546.
E-mail: Jrivier@salk.edu.
(13) Hocart, S. J.; Jain, R.; Murphy, W. A.; Taylor, J. E.; Morgan, B.;
Coy, D. H. Potent antagonists of somatostatin: synthesis and biology.
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Waser, B.; Rivier, J. SST3-selective potent peptidic somatostatin recep-
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(15) Grace, C. R. R.; Erchegyi, J.; Koerber, S. C.; Reubi, J. C.; Rivier,
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Three-dimensional consensus structure by NMR. J. Med. Chem. 2003,
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M. Novel sst5-selective somatostatin dicarba-analogues: synthesis
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’ ABBREVIATIONS USED
AA, amino acid; Agl, aminoglycine; Boc, tert-butoxycarbonyl;
BSA, bovine serum albumin; Bzl, benzyl; Bzl(3Br), 3-bromobenzyl;
Z(2Br), 2-bromobenzyloxycarbonyl; Z(2Cl), 2-chlorobenzylox-
ycarbonyl; Cbm, carbamoyl; CZE, capillary zone electrophore-
sis; DIC, N,N0-diisopropylcarbodiimide; DIPEA, diisopropylethyla-
mine; HOBt, l-hydroxybenzotriazole; ImBzl, Nim-benzyl; Mob,
4-methoxybenzyl; Nal, 3-(2-naphthyl)alanine; NMP, N-methyl-
pyrrolidinone; SRIF, somatostatin; ssts, SRIF receptors; TEA, triethyla-
mine; TEAP, triethylammonium phosphate; TFA, trifluoroacetic acid
’ ADDITIONAL NOTE
(17) Di Cianni, A.; Carotenuto, A.; Brancaccio, D.; Novellino, E.;
Reubi, J. C.; Beetschen, K.; Papini, A. M.; Ginanneschi, M. Novel
octreotide dicarba-analogues with high affinity and different selectivity
for somatostatin receptors. J. Med. Chem. 2010, 53, 6188–6197.
(18) Grace, C. R. R.; Durrer, L.; Koerber, S. C.; Erchegyi, J.; Reubi,
J. C.; Rivier, J. E.; Riek, R. Somatostatin receptor 1 selective analogues: 4.
Three-dimensional consensus structure by NMR. J. Med. Chem. 2005,
48, 523–533.
(19) Grace, C. R. R.; Erchegyi, J.; Koerber, S. C.; Reubi, J. C.; Rivier,
J.; Riek, R. Novel sst2-selective somatostatin agonists. Three-dimen-
sional consensus structure by NMR. J. Med. Chem. 2006, 49, 4487–4496.
(20) Grace, C. R. R.; Erchegyi, J.; Reubi, J. C.; Rivier, J. E.; Riek, R.
Three-dimensional consensus of structure of sst2-selective somatostatin
(SRIF) antagonists by NMR. Biopolymers 2008, 89, 1077–1087.
(21) Rivier, J.; Brown, M.; Vale, W. [D-Trp8]-somatostatin: an
analog of somatostatin more potent than the native molecule. Biochem.
Biophys. Res. Commun. 1975, 65, 746–751.
(22) Vale, W.; Rivier, J.; Ling, N.; Brown, M. Biologic and immu-
nologic activities and applications of somatostatin analogs. Metabolism
1978, 27, 1391–1401.
(23) Bauer, W.; Briner, U.; Doepfner, W.; Haller, R.; Huguenin, R.;
Marbach, P.; Petcher, T. J.; Pless, J. SMS 201-995: a very potent and
selective octapeptide analog of somatostatin with prolonged action. Life
Sci. 1982, 31, 1133–1140.
The abbreviations for the common amino acids are in accordance
with the recommendations of the IUPAC-IUB Joint Commis-
sion on Biochemical Nomenclature (Eur. J. Biochem. 1984, 138,
9ꢀ37). The symbols represent the L-isomer except when in-
dicated otherwise.
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