Allosteric modulators of serotonin and dopamine receptorsnew drugs on GPCRs

Abstract

G protein-coupled receptors (GPCRs) are eukaryotic cell membrane proteins that transduce a wide range of extracellular stimuli into intracellular changes in cell function. Based on their amino acid sequence, they can be classified in four different classes: class A or rhodopsin-like family, class B or secretin-like family, class C or glutamate-like family, and class F or Frizzled receptor-like family.1,2 Activation of GPCRs upon ligand binding in the extracellular side triggers conformational changes that allow the receptor to interact with the corresponding heterotrimeric G protein, which initiates a series of downstream signalling pathways via second messenger molecules. Alternatively, #xF062;-arrestins can act as signalling scaffolds for many GPCR pathways.3 GPCRs represent the largest group of cell surface receptors encoded by the human genome (~2%)4 and have been associated to a multitude of human disorders, which makes them the focus of attention of many drug discovery programs. Traditionally, the development of drugs that target GPCRs has been focused on finding agonists or antagonists that displace the natural or endogenous ligand to activate or inhibit the receptor. Emerging knowledge of structure and physiological functions of GPCRs has begun to alter the approaches to drug discovery.5 Thus, over the past two decades, novel strategies such as the development of biased6 and bitopic ligands,7 allosteric modulators,8,9 pepducins10 or ligands targeting GPCR heteromers11 have appeared (Figure 1). Some of these new approaches have proved to be productive, yielding molecules currently in clinical trials or even marketed. Specifically, allosteric modulators present several advantages in their mechanism of action over “classical” orthosteric ligands, allowing a higher efficacy and selectivity...