A pharmacological primer of biased agonism

Abstract

Biased agonism is one of the fastest growing topics in G protein-coupled receptor pharmacology; moreover, biased agonists are used in the clinic today: carvedilol (Coreg®) is a biased agonist of beta-adrenergic receptors. However, there is a general lack of understanding of biased agonism when compared to traditional pharmacological terminology. Therefore, this review is designed to provide a basic introduction to classical pharmacology as well as G protein-coupled receptor signal transduction in order to clearly explain biased agonism for the non-scientist clinician and pharmacist. Special emphasis is placed on biased agonists of the beta-adrenergic receptors, as these drugs are highly prescribed, and a hypothetical scenario based on current clinical practices and proposed mechanisms for treating disease is discussed in order to demonstrate the need for a more thorough understanding of biased agonism in clinical settings. Since biased agonism provides a novel mechanism for treating disease, greater emphasis is being placed to develop biased agonists; therefore, it is important for biased agonism to be understood in equal measure of traditional pharmacological concepts. This review, along with many others, can be used to teach the basic concepts of biased agonism, and this review also serves to introduce the subsequent reviews that examine, in more depth, the relevance of biased agonism towards the angiotensin type 1 receptor, parathyroid hormone receptor, and natural biased ligands towards chemokine receptors.

Fig. (1)

Depiction of classical pharmacological terminology. Depicted is a typical pharmacological dose-response curve using a linear Y-axis and a Log₁₀ X-axis; the curve that is generated is a sigmoidal curve. The midpoint of the curve (50% response represented by ■) is the effective concentration 50 (EC₅₀), which is used to rank agonists. A compound can have greater or lesser efficacy and potency (shown as shaded arrows).

Fig. (2)

Depiction of classical GPCR initiated signaling and desensitization. All cartoons were created from published crystal structures. (A) Basal state of a GPCR docked to the heterotrimeric Gprotein. (B) Canonical ligand initiated signaling separates and the Gα and Gβγ subunits from each other and the receptor allowing for each to initiate signal transduction cascades. (C) Homologous desensitization is initiated by GRK-dependent phosphorylation of the receptor and signaling-induced phosphorylation of the receptor by PKA or PKC.

Fig. (3)

Modified Venn diagram representing the relationship between GPCR shape and signaling. Receptor shape dictates signaling, and there is only a certain range of shapes that can be formed by a functional GPCR (thick black box). Within those range of shapes some will resulted in no signaling (clear box), some in traditional signaling (cross hatched box), while others in biased agonism of the G-protein (rightward slant) or β-arrestins (leftward slant).