Insights into the structural biology of G-protein coupled receptors impacts drug design for central nervous system neurodegenerative processes  

作　　者：Farfán-García Eunice Dalet Trujillo-Ferrara José Guadalupe Castillo-Hernández María del Carmen Guerra-Araiza Christian Humberto Soriano-Ursúa Marvin Antonio 

机构地区：[1]Escuela Superior de Medicina, Instituto Politécnico Nacional. Plan de San Luis y Díaz Mirón s/n, Col. Casco de Santo Tomas

出　　处：《Neural Regeneration Research》2013年第24期2290-2302,共13页中国神经再生研究（英文版）

基　　金：supported by SIP-IPN,CONACYT (CB-168116);FIS/IMSS (FIS/IMSS/PROT/G11-2/1013)

摘　　要：In the last few years, there have been important new insights into the structural biology of G-protein coupled receptors. It is now known that allosteric binding sites are involved in the affinity and selec- tivity of ligands for G-protein coupled receptors, and that signaling by these receptors involves both G-protein dependent and independent pathways. The present review outlines the physiological and pharmacological implications of this perspective for the design of new drugs to treat disorders of the central nervous system. Specifically, new possibilities are explored in relation to allosteric and or- thosteric binding sites on dopamine receptors for the treatment of Parkinson＇s disease, and on muscarinic receptors for Alzheimer＇s disease. Future research can seek to identify ligands that can bind to more than one site on the same receptor, or simultaneously bind to two receptors and form a dimer. For example, the design of bivalent drugs that can reach homo/hetero-dimers of D2 dopa- mine receptor holds promise as a relevant therapeutic strategy for Parkinson＇s disease. Regarding the treatment of Alzheimer＇s disease, the design of dualsteric ligands for mono-oligomeric mus- carinic receptors could increase therapeutic effectiveness by generating potent compounds that could activate more than one signaling pathway.In the last few years, there have been important new insights into the structural biology of G-protein coupled receptors. It is now known that allosteric binding sites are involved in the affinity and selec- tivity of ligands for G-protein coupled receptors, and that signaling by these receptors involves both G-protein dependent and independent pathways. The present review outlines the physiological and pharmacological implications of this perspective for the design of new drugs to treat disorders of the central nervous system. Specifically, new possibilities are explored in relation to allosteric and or- thosteric binding sites on dopamine receptors for the treatment of Parkinson＇s disease, and on muscarinic receptors for Alzheimer＇s disease. Future research can seek to identify ligands that can bind to more than one site on the same receptor, or simultaneously bind to two receptors and form a dimer. For example, the design of bivalent drugs that can reach homo/hetero-dimers of D2 dopa- mine receptor holds promise as a relevant therapeutic strategy for Parkinson＇s disease. Regarding the treatment of Alzheimer＇s disease, the design of dualsteric ligands for mono-oligomeric mus- carinic receptors could increase therapeutic effectiveness by generating potent compounds that could activate more than one signaling pathway.

关 键 词：neural regeneration G-Protein coupled receptors structural biology drug design neurodegenera-tive disorders   oligomedzation biased signaling Parkinson＇s disease Alzheimer＇s disease dopa-mine receptors muscarinic receptors grants-supported paper NEUROREGENERATION 

分 类 号：R96[医药卫生—药理学]