CNS Biased Agonism and the Promise of Targeting Drugs Beyond Receptors to Cellular Pathways

A fundamental problem of CNS drug discovery is the targeting of specific cells and their functions by drugs that are typically distributed throughout the brain. Drugs that target specific receptors limit effects to cells that display that receptor. However, receptors have different influences in different brain regions, cell types, or cell states. Here, we discuss biased signaling where different ligands provide different activation states of the same receptor. This offers the possibilities of more precise targeting at the level of intracellular pathway preference. We discuss the basis of biased signaling in the stabilization of different conformations of a multistate receptor. We then look at the transducerome, the link between receptor conformation, and effector/pathway influence. Three cases are discussed including an FDA-approved mu-Opioid agonist developed using biased signaling-based drug discovery. Another case demonstrates preclinical biased signaling of the 5-HT1A receptor resulting in brain region selective outcomes. Finally, we discuss efforts using psychedelic drugs targeted at the 5-HT2A receptor using biased agonism to favor therapeutic outcomes with reduced hallucinogenic effects. An additional form of biased signaling, location bias, is discussed.