GABA_B受体变构剂药学研究进展

γ-氨基丁酸B受体（GABAB receptor,GABABR）是最具有药理学意义的药物靶点之一,具有复杂而精细的激活机制。传统的GABABR靶点药物开发集中于激动剂和拮抗剂,这类药物受到多种因素的制约,包括较强的副作用、药物代谢困难、机体耐药性明显等。变构剂结合于正构位点之外,能够调节GABABR异源二聚体亚基或结构域间的相互作用。正向变构剂（positiveallosteric modulators,PAMs）和负向变构剂（negative allosteric modulators,NAMs）分别可以提高或降低GABABR的活性,并具有较高的特异性和药物安全性,同时还能够保持GABABR信号在时间和空间上的可控性。变构剂为GABABR靶点药物开发提供了新思路。

The Progress of Pharmacology of GABAB Receptors Allosteric Modulators

GABAB receptors are a member of the G protein-coupled family of receptors which are generally considered to be excellent drug targets,with a complex and refined mechanism of activation.Traditional drug development targeted at GABAB receptors is focused on agonists and antagonists,the use of which is limited by its side effects,poor pharmacokinetics,and the development of tol-erance.Allosteric modulators,which interact with binding sites topologically distinct from the orthosteric ligand binding sites,can modu-late the interaction between subunits or domains in the GABAB heterodimer.Positive and negative allosteric modulators can potentiate or decrease the activity of GABAB receptors respectively,with improved selectivity and safety,along with maintenance of spatial and tem-poral aspects of GABAB receptors signaling.Allosteric modulators give the new opportunity on the GABAB receptors targeted drug devel-opment.