Discovery and characterization of non-competitive antagonists of group I metabotropic glutamate receptors

被引：23

作者：

Gasparini, F ^{[1
]}

Floersheim, P ^{[1
]}

Flor, PJ ^{[1
]}

Heinrich, M ^{[1
]}

Inderbitzin, W ^{[1
]}

Ott, D ^{[1
]}

Pagano, A ^{[1
]}

Stierlin, C ^{[1
]}

Stoehr, N ^{[1
]}

Vranesic, I ^{[1
]}

Kuhn, R ^{[1
]}

机构：

[1] Novartis Pharma AG, Nervous Syst Res, CH-4002 Basel, Switzerland

来源：

FARMACO | 2001年 / 56卷 / 1-2期

关键词：

metabotropic glutamate receptors; molecular modeling; non-competitive antagonists;

D O I：

10.1016/S0014-827X(01)01008-4

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

We have investigated the mechanism of inhibition of the new group I mGluR antagonists CPCCOEt and MPEP and determined that both compounds have a non-competitive mode of inhibition. Furthermore using chimeric/mutated receptors constructs we have found that these antagonists act at a novel pharmacological site located in the trans-membrane (TM). Specific non-conserved amino acid residues in the TM domain have been identified which are necessary for the inhibition by CPCCOEt and MPEP of the mGlul and mGlu5 receptors, respectively. Using molecular modeling a model of the TM domain was built for both mGlul and mGlu5 receptor subtypes. Docking of CPCCOEt and MPEP into their respective model allowed the modelisation of the novel binding site. (C) 2001 Elsevier Science S.A. All rights reserved.

引用

页码：95 / 99

页数：5

共 13 条

[1] A novel class of antagonists for metabotropic glutamate receptors, 7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxylates [J].

Annoura, H ;

Fukunaga, A ;

Uesugi, M ;

Tatsuoka, T ;

Horikawa, Y .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 1996, 6 (07) :763-766

[2] An alpha-carbon template for the transmembrane helices in the rhodopsin family of G-protein-coupled receptors [J].

Baldwin, JM ;

Schertler, GFX ;

Unger, VM .

JOURNAL OF MOLECULAR BIOLOGY, 1997, 272 (01) :144-164

[3] Pharmacology and functions of metabotropic glutamate receptors [J].

Conn, PJ ;

Pin, JP .

ANNUAL REVIEW OF PHARMACOLOGY AND TOXICOLOGY, 1997, 37 :205-237

[4] 2-methyl-6-(phenylethynyl)-pyridine (MPEP), a potent, selective and systemically active mGlu5 receptor antagonist [J].

Gasparini, F ;

Lingenhöhl, K ;

Stoehr, N ;

Flor, PJ ;

Heinrich, M ;

Vranesic, I ;

Biollaz, M ;

Allgeier, H ;

Heckendorn, R ;

Urwyler, S ;

Varney, MA ;

Johnson, EC ;

Hess, SD ;

Rao, SP ;

Sacaan, AI ;

Santori, EM ;

Veliçelebi, G ;

Kuhn, R .

NEUROPHARMACOLOGY, 1999, 38 (10) :1493-1503

[5] Chiral resolution and stereospecificity of 6-phenyl-4-phenylethynyl-1,4-dihydropyridines as selective A3 adenosine receptor antagonists [J].

Jiang, JL ;

Li, AH ;

Jang, SY ;

Chang, L ;

Melman, N ;

Moro, S ;

Ji, XD ;

Lobkovsky, EB ;

Clardy, JC ;

Jacobson, KA .

JOURNAL OF MEDICINAL CHEMISTRY, 1999, 42 (16) :3055-3065

[6]

Litschig S, 1999, MOL PHARMACOL, V55, P453

[7]

*MOL SIM INC, X PLOR 3 1 SOFTW

[8] THE LIGAND-BINDING DOMAIN IN METABOTROPIC GLUTAMATE RECEPTORS IS RELATED TO BACTERIAL PERIPLASMIC BINDING-PROTEINS [J].

OHARA, PJ ;

SHEPPARD, PO ;

THOGERSEN, H ;

VENEZIA, D ;

HALDEMAN, BA ;

MCGRANE, V ;

HOUAMED, KM ;

THOMSEN, C ;

GILBERT, TL ;

MULVIHILL, ER .

NEURON, 1993, 11 (01) :41-52

[9] Chiral resolution, pharmacological characterization, and receptor docking of the noncompetitive mGlu1 receptor antagonist (±)-2-hydroxyimino-1a,2-dihydro-1H-7-oxacyclopropa[b]naphthalene-7a-carboxylic acid ethyl ester [J].

Ott, D ;

Floersheim, P ;

Inderbitzin, W ;

Stoehr, N ;

Francotte, E ;

Lecis, G ;

Richert, P ;

Rihs, G ;

Flor, PJ ;

Kuhn, R ;

Gasparini, F .

JOURNAL OF MEDICINAL CHEMISTRY, 2000, 43 (23) :4428-4436

[10] The non-competitive antagonists 2-methyl-6-(phenylethynyl)pyridine and 7-hydroxyiminocyclopropan [b]chromen-1α-carboxylic acid ethyl ester interact with overlapping binding pockets in the transmembrane region of group I metabotropic glutamate receptors [J].

Pagano, A ;

Rüegg, D ;

Litschig, S ;

Stoehr, N ;

Stierlin, C ;

Heinrich, M ;

Floersheim, P ;

Prezèau, L ;

Carroll, F ;

Pin, JP ;

Cambria, A ;

Vranesic, I ;

Flor, PJ ;

Gasparini, F ;

Kuhn, R .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2000, 275 (43) :33750-33758

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