Complex Pharmacology of Free Fatty Acid Receptors.
G protein-coupled receptors (GPCRs) are historically the most successful family of drug targets. In recent times it has become clear that the pharmacology of these receptors is far more complex than previously imagined. Understanding of the pharmacological regulation of GPCRs now extends beyond simple competitive agonism or antagonism by ligands interacting with the orthosteric binding site of the receptor to incorporate concepts of allosteric agonism, allosteric modulation, signaling bias, constitutive activity, and inverse agonism. Herein, we consider how evolving concepts of GPCR pharmacology have shaped understanding of the complex pharmacology of receptors that recognize and are activated by nonesterified or "free" fatty acids (FFAs). The FFA family of receptors is a recently deorphanized set of GPCRs, the members of which are now receiving substantial interest as novel targets for the treatment of metabolic and inflammatory diseases. Further understanding of the complex pharmacology of these receptors will be critical to unlocking their ultimate therapeutic potential.
Centre for Translational Pharmacology, Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow , Glasgow G12 8QQ, Scotland, United Kingdom.
Graeme
G
Milligan
Department of Physics, Chemistry and Pharmacy, University of Southern Denmark , Campusvej 55, DK-5230 Odense M, Denmark.
Bharat
B
Shimpukade
Department of Physics, Chemistry and Pharmacy, University of Southern Denmark , Campusvej 55, DK-5230 Odense M, Denmark.
Trond
T
Ulven
Centre for Translational Pharmacology, Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow , Glasgow G12 8QQ, Scotland, United Kingdom.
Brian D
BD
Hudson
D000494:Allosteric Regulation; D000818:Animals; D005230:Fatty Acids, Nonesterified / Q000378:metabolism*; D005456:Fluorescent Dyes / Q000737:chemistry; D006801:Humans; D008024:Ligands; D043562:Receptors, G-Protein-Coupled / Q000187:drug effects* / Q000378:metabolism
D005230:Fatty Acids, Nonesterified; D005456:Fluorescent Dyes; D008024:Ligands; D043562:Receptors, G-Protein-Coupled