Biased ligands at opioid receptors: Current status and future directions

Abstract

The opioid crisis represents a major worldwide public health crisis that has accelerated the search for safer and more effective opioids. Over the past few years, the identification of biased opioid ligands capable of eliciting selective functional responses has provided an alternative avenue to develop novel therapeutics without the side effects of current opioid medications. However, whether biased agonism or other pharmacological properties, such as partial agonism (or low efficacy), account for the therapeutic benefits remains questionable. Here, we provide a summary of the current status of biased opioid ligands that target the μ- and κ-opioid receptors and highlight advances in preclinical and clinical trials of some of these ligands. We also discuss an example of structure-based biased ligand discovery at the μ-opioid receptor, an approach that could revolutionize drug discovery at opioid and other receptors. Last, we briefly discuss caveats and future directions for this important area of research.

Fig. 1. Signaling and regulatory paradigms of opioid receptors.

(Left) Agonist stimulation leads to the coupling of opioid receptors to heterotrimeric G proteins, resulting in a reduction in cAMP abundance, a decreased Ca²⁺ response, and the activation of GIRK channels. (Middle) Subsequently, the receptor is phosphorylated by GRKs, which results in β-arrestin recruitment, receptor desensitization, and internalization. β-Arrestins also mediate the activation of various signaling pathways, including those of the MAPKs, ERK1/2, and p38. (Right) Gα_i protein and β-arrestins can also interact with each other and form a complex to mediate downstream signaling, such as ERK activation.

Fig. 2. Chemical space shared by the currently reported G protein–biased ligands at μ-OR and ĸ-OR.

(A) Chemical structures of currently described G protein–biased ligands at the μ-OR and ĸ-OR. Of these, nalfurafine shows moderate selectivity at ĸ-OR compared with μ-OR and δ-OR, whereas the others exhibit substantial selectivity for the different receptors. (B) The different types of ligand bias that can be potentially manifested by opioid receptors.

Fig. 3. Structure-based discovery and optimization of a G protein–biased μ-OR ligand, PZM21.

Schematic representation of the discovery and optimization pipeline using structure-guided virtual screening. Using the crystal structure of the μ-OR, a large set of chemical compounds was virtually screened, which was followed by the identification of a handful of lead compounds for further testing. Subsequent optimization and structure-function relationship studies yielded PZM21, which is a G protein–biased μ-OR partial agonist, and produced desirable analgesic activity in vivo without the typical side effects observed with other μ-OR agonists, such as morphine.