Inverse agonism at heptahelical receptors: concept, experimental approach and therapeutic potential

被引:32
作者
Daeffler, L [1 ]
Landry, Y [1 ]
机构
[1] Univ Strasbourg 1, INSERM, U425, Fac Pharm,Lab Neuroimmunopharmacol, F-67401 Illkirch Graffenstaden, France
关键词
inverse agonist; G protein; two-state model; ternary complex model; constitutively active receptor;
D O I
10.1111/j.1472-8206.2000.tb00395.x
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Inverse agonists (negative antagonists) are ligands that stabilize the inactive conformation (R) of receptors according to the two-stale receptor model. The active conformation (R*) of heptahelical receptors, i.e. G protein-coupled receptors, has high affinity for G proteins. According to ternary complex models of receptor activation, the R*G complex is in equilibrium with R + G, with spontaneous activity in the absence of agonist. Inverse agonists, having a higher affinity for R, shift R*G towards R + G, decreasing the spontaneous activity of receptors. Agonists have the opposite effect, with a higher afiinity for R*. Neutral antagonists have the same affinity for R and R* and compete for both agonists and inverse agonists. Inverse agonists have been recently proposed for a variety of heptahelical receptors. Methods to detect inverse agonists among antagonists are based on the determination of ligand affinity at R and R* with binding experiments, and on the modulation of G protein activity (GTP binding and hydrolysis) or of effector activity. Receptor inverse agonists, but also G protein antagonists and GTPase inhibitors, decrease spontaneous G protein activity corresponding to R*G. Receptor agonists, G protein agonists and GTPase inhibitors increase effector basal activity, but receptor inverse agonists decrease it. The therapeutic potential of inverse agonists is proposed in human diseases ascribed to constitutively active mutant receptors and may be extended to diseases related to wild-type receptor over-expression leading to the increase of R*. Some of the therapeutic effects of presently used receptor antagonists may be related to their inverse agonist properties. Inverse agonists lead to receptor upregulation, offering new approaches to tolerance and dependence to drugs. (C) 2000 Editions scientifiques et medicales Elsevier SAS.
引用
收藏
页码:73 / 87
页数:15
相关论文
共 121 条
[1]  
ABOOD ME, 1982, J BIOL CHEM, V257, P540
[2]   G-PROTEIN-COUPLED RECEPTOR GENES AS PROTOONCOGENES - CONSTITUTIVELY ACTIVATING MUTATION OF THE ALPHA-1B-ADRENERGIC RECEPTOR ENHANCES MITOGENESIS AND TUMORIGENICITY [J].
ALLEN, LF ;
LEFKOWITZ, RJ ;
CARON, MG ;
COTECCHIA, S .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1991, 88 (24) :11354-11358
[3]   EXOCYTOSIS IN MAST-CELLS BY BASIC SECRETAGOGUES - EVIDENCE FOR DIRECT ACTIVATION OF GTP-BINDING PROTEINS [J].
ARIDOR, M ;
TRAUB, LM ;
SAGIEISENBERG, R .
JOURNAL OF CELL BIOLOGY, 1990, 111 (03) :909-917
[4]  
ARIENS EJ, 1954, ARCH INT PHARMACOD T, V99, P32
[5]   Human herpesvirus KSHV encodes a constitutively active G-protein-coupled receptor linked to cell proliferation [J].
Arvanitakis, L ;
GerasRaaka, E ;
Varma, A ;
Gershengorn, MC ;
Cesarman, E .
NATURE, 1997, 385 (6614) :347-350
[6]   G-protein-coupled receptor of Kaposi's sarcoma-associated herpesvirus is a viral oncogene and angiogenesis activator [J].
Bais, C ;
Santomasso, B ;
Coso, O ;
Arvanitakis, L ;
Raaka, EG ;
Gutkind, JS ;
Asch, AS ;
Cesarman, E ;
Gerhengorn, MC ;
Mesri, EA .
NATURE, 1998, 391 (6662) :86-89
[7]  
BARKER EL, 1994, J BIOL CHEM, V269, P11687
[8]   PHOSDUCIN IS A PROTEIN KINASE-A-REGULATED G-PROTEIN REGULATOR [J].
BAUER, PH ;
MULLER, S ;
PUZICHA, M ;
PIPPIG, S ;
OBERMAIER, B ;
HELMREICH, EJM ;
LOHSE, MJ .
NATURE, 1992, 358 (6381) :73-76
[9]   Mammalian RGS proteins: Barbarians at the gate [J].
Berman, DM ;
Gilman, AG .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1998, 273 (03) :1269-1272
[10]   GUANINE-NUCLEOTIDES MODULATE MUSCARINIC RECEPTOR-BINDING IN THE HEART [J].
BERRIE, CP ;
BIRDSALL, NJM ;
BURGEN, ASV ;
HULME, EC .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1979, 87 (04) :1000-1005