Evaluation of lactam-bridged neurotensin analogues adjusting ψ(Pro10) close to the experimentally derived bioactive conformation of NT(8-13)

被引：37

作者：

Bittermann, H ^{[1
]}

Einsiedel, J ^{[1
]}

Hübner, H ^{[1
]}

Gmeiner, P ^{[1
]}

机构：

[1] Univ Erlangen Nurnberg, Emil Fischer Ctr, Dept Med Chem, D-91052 Erlangen, Germany

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2004年 / 47卷 / 22期

关键词：

D O I：

10.1021/jm049644y

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The neurotensin C-terminal hexapeptide, NT(8-13), which has been found to adopt a beta-strand-like conformation while bound to the NT1 receptor, was modified by the introduction of conformational constraints. Synthesis of the four stereoisomeric 4.4-spirolactams 1-4 and subsequent NT1 receptor binding studies showed that the restriction of Psi(Pro(10)) to approximately 130degrees leads to a more than 1000-fold increase of binding affinity for 1 (K-i = 12 nM) when compared to the more flexible analogue [NMeTyr(11)]NT(8-13).

引用

页码：5587 / 5590

页数：4

共 28 条

[21] ALKYLATION OF AMINO-ACIDS WITHOUT LOSS OF THE OPTICAL-ACTIVITY - PREPARATION OF ALPHA-SUBSTITUTED PROLINE DERIVATIVES - A CASE OF SELF-REPRODUCTION OF CHIRALITY
SEEBACH, D
BOES, M
NAEF, R
SCHWEIZER, WB
[J]. JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1983, 105 (16) : 5390 - 5398
[22] DESIGN AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF C-TERMINAL CYCLIC NEUROTENSIN FRAGMENT ANALOGS
SEFLER, AM
HE, JX
SAWYER, TK
HOLUB, KE
OMECINSKY, DO
REILY, MD
THANABAL, V
AKUNNE, HC
CODY, WL
[J]. JOURNAL OF MEDICINAL CHEMISTRY, 1995, 38 (02) : 249 - 257
[23] The effects of systemic NT69L, a neurotensin agonist, on baseline and drug-disrupted prepulse inhibition
Shilling, PD
Richelson, E
Feifel, D
[J]. BEHAVIOURAL BRAIN RESEARCH, 2003, 143 (01) : 7 - 14
[24] Conformational analysis of reverse-turn constraints by N-methylation and N-hydroxylation of amide bonds in peptides and non-peptide mimetics
Takeuchi, Y
Marshall, GR
[J]. JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1998, 120 (22) : 5363 - 5372
[25] Neurotensin: peptide for the next millennium
Tyler-McMahon, BM
Boules, M
Richelson, E
[J]. REGULATORY PEPTIDES, 2000, 93 (1-3) : 125 - 136
[26] Wang H, 1999, SYNLETT, P33
[27] POTENT AND HIGHLY SELECTIVE NEUROKININ ANTAGONISTS
WARD, P
EWAN, GB
JORDAN, CC
IRELAND, SJ
HAGAN, RM
BROWN, JR
[J]. JOURNAL OF MEDICINAL CHEMISTRY, 1990, 33 (07) : 1848 - 1851
[28] WARD P, 1992, Patent No. 5166136

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