GPCR homomers and heteromers: A better choice as targets for drug development than GPCR monomers?

被引：76

作者：

Casado, Vicent ^{[1
,2
]}

Cortes, Antoni ^{[1
,2
]}

Mallol, Josefa ^{[1
,2
]}

Perez-Capote, Kamil ^{[1
,2
]}

Ferre, Sergi ^{[3
]}

Lluis, Carmen ^{[1
,2
]}

Franco, Rafael ^{[1
,2
]}

Canela, Enric I. ^{[1
,2
]}

机构：

[1] Univ Barcelona, Dept Bioquim & Biol Mol, CIBERNED, Ctr Invest Red Enfermedades Neurodegenerat, E-08028 Barcelona, Spain

[2] Univ Barcelona, IDIBAPS, E-08028 Barcelona, Spain

[3] Natl Inst Drug Abuse, IRP, NIH, DHHS, Baltimore, MD 21224 USA

来源：

PHARMACOLOGY & THERAPEUTICS | 2009年 / 124卷 / 02期

关键词：

Equilibrium constants; Binding assays; Cooperativity; G protein-coupled receptors; Receptor heteromers; Receptor dimers; PROTEIN-COUPLED RECEPTORS; DELTA-OPIOID RECEPTORS; A(1) ADENOSINE RECEPTORS; TERNARY COMPLEX MODEL; ALLOSTERIC MODULATION; NEGATIVE COOPERATIVITY; DOPAMINE-D-2; RECEPTORS; MOLECULAR-MECHANISMS; MORPHINE-TOLERANCE; BINDING-PROPERTIES;

D O I：

10.1016/j.pharmthera.2009.07.005

中图分类号：

R9 [药学];

学科分类号：

100702 [药剂学];

摘要：

G protein-coupled receptors (GPCR) are targeted by many therapeutic drugs marketed to fight against a variety of diseases. Selection of novel lead compounds are based on pharmacological parameters obtained assuming that GPCR are monomers. However, many GPCR are expressed as dimers/oligomers. Therefore, drug development may consider GPCR as homo- and hetero-oligomers. A two-state dimer receptor model is now available to understand GPCR operation and to interpret data obtained from drugs interacting with dimers, and even from mixtures of monomers and dimers. Heteromers are distinct entities and therefore a given drug is expected to have different affinities and different efficacies depending on the heteromer. All these concepts would lead to broaden the therapeutic potential of drugs targeting GPCRs, including receptor heteromer-selective drugs with a lower incidence of side effects, or to identify novel pharmacological profiles using cell models expressing receptor heteromers. (C) 2009 Elsevier Inc. All rights reserved.

引用

页码：248 / 257

页数：10

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