GPCR homomers and heteromers: a better choice as targets for drug development than GPCR monomers?
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.
Casadó
Vicent
V
Departament de Bioquímica i Biologia Molecular, CIBERNED (Centro de Investigación en Red de Enfermedades Neurodegenerativas) and Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) Universitat de Barcelona, 08028 Barcelona, Catalonia, Spain.
Cortés
Antoni
A
Mallol
Josefa
J
Pérez-Capote
Kamil
K
Ferré
Sergi
S
Lluis
Carmen
C
Franco
Rafael
R
Canela
Enric I
EI
D000818:Animals; D016503:Drug Delivery Systems / Q000639:trends*; D055808:Drug Discovery / Q000639:trends*; D006801:Humans; D011485:Protein Binding / Q000502:physiology; D055503:Protein Multimerization / Q000187:drug effects / Q000502:physiology; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*
D043562:Receptors, G-Protein-Coupled