Figure 1.

The schematic depicts the predicted outcome of comparing a conventional drug to a biased drug in vivo where the conventional agonist promotes ‘Response 1’ while this response is absent when the animal is treated with the biased agonist. To distinguish a biased agonist from an inactive compound (or antagonist), both agonists should be similarly efficient at promoting a different response attributable to the receptor’s activation (Response 2). An example of biased agonism and alternative happenings are presented in the figure. (a) The depiction of biased agonism wherein the conventional agonist (orange starburst) binds to the receptor to induce Responses 1 and 2 and the biased agonist (blue star) only engages signaling at the receptor that leads to Response 2. (b) Alternatively, the ‘biased agonist’ could have activity at another target that opposes the actions it has at the primary target associated with Response 1. (c) This could also happen if the ‘biased agonist’ is metabolized in vivo to form a new compound that does not preserve the pharmacology of the parent compound (i.e. it could become an antagonist and competitively prevent Response 1. Moreover, the metabolite could simply be less potent and efficacious than the parent compound. (d) Additionally, if the ‘biased agonist’ has a different bioavailability profile than the conventional agonist in vivo, then the lack of its activity in Response 1 could be attributed to its inability to reach the target receptor that controls the response. In this example, the ‘biased agonist’ does not cross the blood–brain barrier efficiently and therefore, cannot reach the target receptor. In the examples of b–d, the ‘biased agonist’ would have non-selective effects rather than be considered functionally selective at the target GPCR and therefore, not a ‘biased agonist’.