Development of an orexin-2 receptor selective agonist, [Ala11, D-Leu15]orexin-B

被引：82

作者：

Asahi, S ^{[1
]}

Egashira, SI ^{[1
]}

Matsuda, M ^{[1
]}

Iwaasa, H ^{[1
]}

Kanatani, A ^{[1
]}

Ohkubo, M ^{[1
]}

Ihara, M ^{[1
]}

Morishima, H ^{[1
]}

机构：

[1] Banyu Pharmaceut Co Ltd, Banyu Tsukuba Res Inst, Tsukuba, Ibaraki 3002611, Japan

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2003年 / 13卷 / 01期

关键词：

D O I：

10.1016/S0960-894X(02)00851-X

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Investigation of L-alanine and D-amino acid replacement of orexin-B revealed that three L-leucine residues at the positions of 11, 14, and 15 in orexin-B were important to show selectivity for the orexin-2 receptor (OX2) over the orexin-1 receptor (OX,). L-Alanine substitution at position 11 and D-leucine substitution at positions 14 and 15 maintained the potency of orexin-B to mobilize [Ca2+](i) in CHO cells expressing the OX2, while their potency for the OX, was significantly reduced. In combined substitutions, we identified that [Ala(11), D-Leu(15)]orexin-B showed a 400-fold selectivity for the OX2 (EC50=0.13 nM) over OX1 (EC50 =52nM). [Ala(11), D-Leu(15)]orexin-B is a beneficial tool for addressing the functional roles of the OX2. (C) 2002 Elsevier Science Ltd. All rights reserved.

引用

页码：111 / 113

页数：3

共 13 条

[1] Narcolepsy in orexin knockout mice:: Molecular genetics of sleep regulation [J].

Chemelli, RM ;

Willie, JT ;

Sinton, CM ;

Elmquist, JK ;

Scammell, T ;

Lee, C ;

Richardson, JA ;

Williams, SC ;

Xiong, YM ;

Kisanuki, Y ;

Fitch, TE ;

Nakazato, M ;

Hammer, RE ;

Saper, CB ;

Yanagisawa, M .

CELL, 1999, 98 (04) :437-451

[2] Structure-activity analysis of truncated orexin-A analogues at the orexin-1 receptor [J].

Darker, JG ;

Porter, RA ;

Eggleston, DS ;

Smart, D ;

Brough, SJ ;

Sabido-David, C ;

Jerman, JC .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2001, 11 (05) :737-740

[3] A selective orexin-1 receptor antagonist reduces food consumption in male and female rats [J].

Haynes, AC ;

Jackson, B ;

Chapman, H ;

Tadayyon, M ;

Johns, A ;

Porter, RA ;

Arch, JRS .

REGULATORY PEPTIDES, 2000, 96 (1-2) :45-51

[4] Effect of lateral cerebroventricular injection of the appetite-stimulating neuropeptide, orexin and neuropeptide Y, on the various behavioral activities of rats [J].

Ida, T ;

Nakahara, K ;

Katayama, T ;

Murakami, N ;

Nakazato, M .

BRAIN RESEARCH, 1999, 821 (02) :526-529

[5] Solution structure of a new hypothalamic neuropeptide, human hypocretin-2/orexin-B [J].

Lee, LH ;

Bang, E ;

Chae, KJ ;

Kim, JY ;

Lee, DW ;

Lee, W .

EUROPEAN JOURNAL OF BIOCHEMISTRY, 1999, 266 (03) :831-839

[6] The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene [J].

Lin, L ;

Faraco, J ;

Li, R ;

Kadotani, H ;

Rogers, W ;

Lin, XY ;

Qiu, XH ;

de Jong, PJ ;

Nishino, S ;

Mignot, E .

CELL, 1999, 98 (03) :365-376

[7] Independent feeding and metabolic actions of orexins in mice [J].

Lubkin, M ;

Stricker-Krongrad, A .

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1998, 253 (02) :241-245

[8] Distribution of orexin neurons in the adult rat brain [J].

Nambu, T ;

Sakurai, T ;

Mizukami, K ;

Hosoya, Y ;

Yanagisawa, M ;

Goto, K .

BRAIN RESEARCH, 1999, 827 (1-2) :243-260

[9] Requirement of intact disulfide bonds in orexin-A-induced stimulation of gastric acid secretion that is mediated by OX1 receptor activation [J].

Okumura, T ;

Takeuchi, S ;

Motomura, W ;

Yamada, H ;

Egashira, S ;

Asahi, S ;

Kanatani, A ;

Ihara, M ;

Kohgo, Y .

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 2001, 280 (04) :976-981

[10]

Pu S, 1998, REGUL PEPTIDES, V78, P133

← 1 2 →