Modulation of 5-HT7R activity has been the focus of numerous drug discovery and development programs [14, 15]. 5-HT7R is a member of the rhodopsin-like family of GPCRs, which counts more than 800 members in human making them a major class of drug targets: 40% of currently prescribed drug targets are GPCRs [16, 17]. However, identification of highly specific ligand is not a trivial task since GPCRs share a common 3D structure (heptahelical transmembrane domains). Though several 5-HT7R antagonists have been successfully developed during the past two decades, tested agonists often suffer from lack of specificity or a poor ability to cross the blood brain barrier (BBB). These are poor characteristics for a potential drug to be developed for central nervous system targets. To date, there are no approved medications targeted specifically to 5-HT7R. However, compounds with interesting pharmacokinetic properties have recently been developed as pain killers in different preclinical models [18, 19].
Defined by McKinnon in 2001 [20] and IUPHAR [21], biased signalling has emerged as a new paradigm in GPCR pharmacology. Biased ligands are molecules which stabilize subsets of receptor conformations that exhibit a unique spectrum of pharmacological responses by specifically targeting G protein or -arrestin signalling [22]. Because they selectively modulate a subset of receptor functions, biased ligands may optimize therapeutic action and generate less pronounced side effects than compounds globally affecting receptor activity [23]. The duration of the drug-target complex, or residence time, seems to be a key determinant in their action mechanism and should be taken into consideration in modern drug discovery [24].
The host team has recently identified a 5-HT7R biased ligand, named Serodolin. Detailed pharmacological characterization of Serodolin revealed that it displays unexpected properties. Serodolin acts as a potent antagonist on the Gs coupled/cAMP pathway (EC50 = 5 nM) but as an agonist on the ERK pathway. We demonstrated that this last effect is not mediated through G proteins but engages −arrestin-2 recruitment [18]. More interestingly, we validated that this unprecedented biased effect on 5-HT7R is not observed for other compounds utilized as 5-HT7R ligands, demonstrating that the pharmacological behaviour of the Serodolin chemical family was unique [18]. Work done by members of this proposed consortium support these findings. Studied in the cardiovascular system, serodolin was unable to cause vasorelaxation or a fall in blood pressure, but acted as a 5-HT7R antagonist [25]. This suggested that Gs but not -arrestin biased agonists could be useful in reducing blood pressure. This new drug may be of interest to investigate the contribution of each pathway (Gs versus −arrestin) in physiological functions. An open question that could be addressed by this consortium is: “What are the promises and limitations of biased ligands of 5-HT7R?”