Reverse Pharmacology

From the early days of GPCR cDNA cloning in the late 1980s until now, the reverse pharmacology strategy participated in the deorphanization of 7TM proteins [6]. The dopamine D2 and the serotonin 5-HT1A receptor were the first GPCRs that were deorphanized by the reverse pharmacology approach 1 8, 13] with many others following over the years (Table 7.1) 1 14-19] . The approach is based on exogenous expression of orphan 7TM proteins in a suitable cell system. Receptors are typically stably overexpressed in model cell lines (i.e., Chinese hamster ovary [CHO] cells) and the activation of hetero-trimeric G protein- dependent pathways are monitored (Fig. 7.1). Receptor overexpression lead also to the discovery that many 7TM proteins are consti-tutively active.

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