TGR5 is a lipid G-protein-coupled receptor (GPCR) endogenously activated by bile acids (BAs). The scientific interest in TGR5 is continuously rising since it has been implicated in mediating the so termed non genomic actions of BAs, which include immunosuppressive properties, regulation of glucose metabolism and energy homeostasis. Genetic and molecular studies combined with the availability of selective ligands have thrust TGR5 into the limelight as an attractive therapeutic target in the arena of metabolic disorders, including type-2 diabetes (T2D). Beginning with an introduction on the early pharmacological characterization, structure and so far disclosed physiological functions of TGR5, this chapter will discuss the therapeutic opportunity of TGR5 modulation in T2D, reporting the endeavours done to date in the development, structure-activity relationships and molecular modelling of TGR5 ligands. In the last part of the chapter, unsettled questions concerning TGR5 modulation are also discussed in the light of the emerging complexity of GPCR modulation.
TGR5 Agonists in Development. Small Molecule Approaches
MACCHIARULO, Antonio;GIOIELLO, ANTIMO;PELLICCIARI, Roberto
2012
Abstract
TGR5 is a lipid G-protein-coupled receptor (GPCR) endogenously activated by bile acids (BAs). The scientific interest in TGR5 is continuously rising since it has been implicated in mediating the so termed non genomic actions of BAs, which include immunosuppressive properties, regulation of glucose metabolism and energy homeostasis. Genetic and molecular studies combined with the availability of selective ligands have thrust TGR5 into the limelight as an attractive therapeutic target in the arena of metabolic disorders, including type-2 diabetes (T2D). Beginning with an introduction on the early pharmacological characterization, structure and so far disclosed physiological functions of TGR5, this chapter will discuss the therapeutic opportunity of TGR5 modulation in T2D, reporting the endeavours done to date in the development, structure-activity relationships and molecular modelling of TGR5 ligands. In the last part of the chapter, unsettled questions concerning TGR5 modulation are also discussed in the light of the emerging complexity of GPCR modulation.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
