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Titolo:
N-methyl scan of somatostatin octapeptide agonists produces interesting effects on receptor subtype specificity
Autore:
Rajeswaran, WG; Hocart, SJ; Murphy, WA; Taylor, JE; Coy, DH;
Indirizzi:
Tulane Univ, Hlth Sci Ctr, Dept Med, Peptide Res Labs, New Orleans, LA 70112 USA Tulane Univ New Orleans LA USA 70112 Res Labs, New Orleans, LA 70112 USA Biomeasure Inc, Milford, MA 01757 USA Biomeasure Inc Milford MA USA 01757Biomeasure Inc, Milford, MA 01757 USA
Titolo Testata:
JOURNAL OF MEDICINAL CHEMISTRY
fascicolo: 9, volume: 44, anno: 2001,
pagine: 1416 - 1421
SICI:
0022-2623(20010426)44:9<1416:NSOSOA>2.0.ZU;2-6
Fonte:
ISI
Lingua:
ENG
Soggetto:
FUNCTIONAL EXPRESSION; SELECTIVE AGONISTS; MOLECULAR-CLONING; GROWTH-HORMONE; ANALOGS; PEPTIDES; POTENT; IDENTIFICATION; OCTREOTIDE; PROTEINS;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
35
Recensione:
Indirizzi per estratti:
Indirizzo: Coy, DH Tulane Univ, Hlth Sci Ctr, Dept Med, Peptide Res Labs, SL12,1430 Tulane Ave, New Orleans, LA 70112 USA Tulane Univ SL12,1430 Tulane Ave New Orleans LA USA 70112 0112 USA
Citazione:
W.G. Rajeswaran et al., "N-methyl scan of somatostatin octapeptide agonists produces interesting effects on receptor subtype specificity", J MED CHEM, 44(9), 2001, pp. 1416-1421

Abstract

The search for synthetic analogues of somatostatin which exhibit selectiveaffinities for the five receptor subtypes is of considerable basic and therapeutic interest and has generated a large number of potent agonist analogues with a wide spectrum of binding profiles. In the past, conformational restriction of side chain groups and the peptide backbone has yielded the most interesting results. Under the latter category and as part of the present study, we were interested in the potential effects of N-methylation of peptide bond NH groups on binding affinity since this approach had not been systematically examined with these peptides. This was aided by new chemistries for introducing an N-Me group during regular solid-phase peptide synthesis using Boc protection. A number of interesting effects were noted on relative binding affinities of the two series of agonist sequences chosen, DPhe(5)(or Tyr(5))-c[Cys(6)-Phe(7)-DTrp(8)-Lys(9)-Thr(10)-Cys(11)]Thr(12)-NH2 (SRIF numbering), at the five known human somatostatin receptors transfectedinto and stably expressed by CHO cells. N-Methylation of residues 7 (Phe),10 (Thr), 11 (Cys), and 12 (Thr) largely destroyed affinities for all fivereceptors. N-Methylation of DTrp in the DPhe series gave an analogue with extraordinarily high affinity for the type 5 receptor for which it was alsoquite selective. N-Methylation of Lys in both series resulted in retentionof type 2 affinity despite this residue constituting the "active center" of somatostatin peptides. N-Methylation of either the N-terminal Tyr residueor of Cys(6) in the Tyr series resulted in analogues with extraordinarily high affinity for the type 3 receptor, also with a degree of specificity. N-Methylation of the peptide bond constrains the conformational space of theamino acid and eliminates the possibility of donor hydrogen bond formationfrom the amide linkage. The beta -bend conformation of the agonists aroundDTrp-Lys is stabilized by a transannular intramolecular hydrogen bond(s) between Phe(7) and Thr(10) so methylation of these residues eliminates this source of stabilization. It is expected that several of these analogues will provide additional tools for determining some of the physiological roles played by type 3 and 5 somatostatin receptors which are still far from being fully elucidated.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 31/03/20 alle ore 19:37:07