G protein-coupled receptors (GPCRs) are the largest superfamily of transmembrane proteins and due to their ubiquitous expression and vast array of functions they present attractive targets for the treatment of a wide number of diseases and disorders. Accordingly, they represent up to 30% of targets of current therapeutics (Overington et al., 2006). Despite the capacity of GPCRs to modulate many (patho-)physiological functions there is a high attrition rate with regard to new compounds entering clinical trials. There are many reasons for the number of failed drug-like compounds such as non-specificity, unfavourable pharmacokinetic profile and lack of clinical efficacy. In this regard, molecules targeting neurotransmitter receptors in the CNS traditionally have poor side-effect profiles due to the high concentrations required to pass the blood-brain barrier. There remain many specific challenges in drug discovery such as promiscuous GPCR-effector coupling; differential celland tissue-specific effects; ligand-induced changes in receptor trafficking; and proteinprotein interactions and receptor oligomerisation (Galandrin et al., 2007; Hanyaloglu and von Zastrow, 2008; Kniazeff et al., 2011; Wettschureck and Offermanns, 2005).