In 2012, the Nobel Prize in Chemistry was awarded to Robert J. Lefkowitz, Howard Hughes Medical Institute/Duke University Medical Center, and Brian K. Kobilka, Stanford University School of Medicine, for “groundbreaking discoveries that reveal the inner workings of… G-protein-coupled receptors” (

G-protein-coupled receptors are a group of proteins consisting of seven transmembrane strands that connect receptors on the inside and outside of the cell membrane. These proteins serve the vital function of allowing communication between the intra- and extracellular environments. G-protein-coupled receptors represent the largest family of mammalian proteins, and their dysfunction is at the core of a number of pathologies (Signal Transduct Target Ther 2021;6:7).

Structurally, G-protein-coupled receptors comprise three distinct portions: the transmembrane domain, which includes seven alpha-helices that span the lipid bilayer of the cell membrane; the extracellular or the N-terminal domain, consisting of three loops; and the intracellular or C-terminal domain, also consisting of three loops.

The extracellularly facing portions of G-protein-coupled receptors can be stimulated by a number of different stimuli, including proteins, gases, neurotransmitters, amino acids, metal ions, and even light (photons) (Curr Opin Struct Biol 2019;57:196-203). Upon stimulation, a change is induced in the shape of the protein. The change translates to an action within the interior-facing portion of the G-protein-coupled receptor.

On the interior of the cell, the external signal can be coupled to different G proteins, or other proteins, termed arrestins, which can result in signaling via cyclic AMP (cAMP), inositol triphosphate, diacylglycerol, release of calcium ions, or the phosphorylation of protein kinases. This initial signaling by extracellular compounds is then translated to internal secondary signaling and ultimately leads to the physiological response.

The G-protein-coupled receptors present in humans are grouped into four different classes, based on their amino acid sequences: “A (rhodopsin), B (secretin and adhesion), C (glutamate), and F (Frizzled)” (Signal Transduct Target Ther. 2021;6:7; Nat Rev Drug Discov. 2019;18:59-82). So far, we have identified more than 800 human G-protein-coupled receptors. Of these, roughly 350 are deemed “druggable,” meaning that they are potential therapeutic targets. Nearly half of the druggable G-protein-coupled receptors have been validated as legitimate clinical targets.

More than 500 FDA-approved drugs currently target G-protein-coupled receptors. As of 2021, approximately 60 compounds are also currently undergoing evaluation in clinical studies as G-protein-coupled receptor-targeted therapies (Nat Rev Drug Discov 2019;18:59-82).

The opioid receptors are a group of class A G-protein-coupled receptors. There are three opioid receptor subtypes: delta (δ), kappa (κ), and mu (μ). Clinically, many opioid-based therapies selectively target the μ-opioid receptor. When activated, the μ-opioid receptor signals via the G-protein (Gαi/o and Gβγ complex) or β-arrestin (Trends Pharmacol Sci 2020;41:947-59). The Nobel Prize in Chemistry was awarded because Drs. Lefkowitz and Kobilka demonstrated how a ligand binds to the μ-opioid receptor can influence the balance between the drug effect coupled to the G-protein and the drug effect coupled to β-arrestin (Sci Signal 2021;14:677).

Once the μ-opioid receptor has been bound to a ligand, G-protein recruitment elicits biological effects such as analgesia, euphoria, and drug dependence. Recruitment of β-arrestin elicits biological effects such as respiratory depression, constipation, nausea, and vomiting (J Pharmacol Exp Ther 2017;361:341-8). Thus, it is thought that drug candidates with a bias towards G-protein recruitment would maximize the analgesia while minimizing some of the harmful side effects associated with β-arrestin recruitment.

The drug tramadol is administered as an oral tablet of two enantiomers ((+)- and (-)-tramadol). Following systemic absorption and metabolism, both enantiomers are converted into (+)- and (-)-desmetramadol by CYP2D6 (Front Pharmacol 2020; 10:1680). Tramadol itself only weakly binds the μ-opioid receptor. Analgesia from tramadol is attributed to μ-opioid receptor agonism of (+)-desmetramadol. Interestingly, (+)-desmetramadol mostly spares β-arrestin recruitment. As a result, this (+)-tramadol metabolite is likely the first “biased opioid” that selectively elicits the G-protein-coupled opioid physiology versus the β-arrestin side effects. As noted by Zebala and colleagues, “relative to morphine {tramadol} is comparable to other G-protein biased μ-opioid receptor agonists, including the clinically tested oliceridine” (Front Pharmacol 2020;10:1680). Because of its dependence upon CYP2D6 for conversion to the biologically active desmetramadol, tramadol has a delayed onset in patients with normal CYP2D6 and may be completely ineffective in patients with CYP2D6 polymorphisms.

“Biased opioids may be as close as we ever get to the holy grail of opioid pharmacology. However, the advances are not limited to opioids. As Porter-Stransky and Weinshenker note, ‘biased agonism complicates G-protein-coupled receptor activity, as different agonists at the same receptor can have opposing effects on physiology.’”

One of the most studied compounds in the biased μ-opioid receptor agonist realm is oliceridine (TRV-130) (J Med Chem 2013;56:8019-31). Medicinal chemistry and initial animal studies suggested that oliceridine was a biased μ-opioid receptor ligand with morphine-like analgesia but with a reduced risk of opioid-induced respiratory depression.

Oliceridine has a complex regulatory history. In 2018, the FDA narrowly declined (in an 8-7 vote) to approval oliceridine for clinical use. The FDA cited cardiac issues (Qt elongation) in their decision. However, they were also not convinced that it caused less respiratory depression in the clinical studies. In August 2020, the FDA approved oliceridine for “the management of moderate to severe acute pain in adults, where the pain is severe enough to require an intravenous opioid and for whom alternative treatments are inadequate” ( This approval was for the short-term usage of intravenous oliceridine “in hospitals or other controlled clinical settings, such as during inpatient and outpatient procedures” but not for at-home administration. Notably, oliceridine retains the black box warning for opioid side effects, including life-threatening respiratory depression.

Trevena, the company that developed oliceridine, is also developing an oral biased opioid, TRV734 (Clin Pharmacol Drug Dev 2020;9:256-66). Preclinical studies demonstrated that TRV734 is a potent analgesic with reduced constipation risk relative to morphine. A first-in-human phase I study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of TRV734 in healthy individuals (Clin Pharmacol Drug Dev 2022;11: 51-62). TRV734 was generally well-tolerated. The analgesia observed was similar to that of 10 mg immediate-release oxycodone.

Another biased μ-opioid receptor ligand is the compound PZM21 (Nature 2016;537:185-90). In their initial paper in Nature, the authors noted PZM21 was “more efficacious for the affective component of analgesia versus the reflexive component and is devoid of both respiratory depression and morphine-like reinforcing activity in mice at equianalgesic doses.” Despite this promising initial report, subsequent studies found that PZM21 dose-dependently depressed respiration “in a manner similar to morphine, the classical opioid receptor agonist” (Br J Pharmacol 2018;175:2653-61).

Given its lack of selectivity for G-protein signaling, exploratory studies were undertaken, including the use of cryo-electron microscopy, to identify analogs of PZM21 that had diminished β-arrestin recruitment (Chem Int Ed Engl 2022;61:26). These studies led to the identification of FH210 as a potential clinical lead.

The curse of opioids is that they can relieve almost any acute pain. No other systemic drug comes close to the analgesic efficacy of opioids. To the best of the authors’ knowledge, there are no drugs of any class in preclinical or clinical development that are as effective analgesics as opioids.

Opioids have an extraordinary list of toxicities, including pruritis, ileus, itching, nausea, vomiting, urinary retention, respiratory depression, addiction, and death. This list of toxicities would be unacceptable with any other class of drugs. Opioids remain a mainstay of anesthetic and pain management for the simple reason that they work. In the case of severe pain, we often simply have no alternatives.

One of the holy grails of opioid research is finding an opioid that does not cause respiratory depression. Decades ago, it was hoped that identification of the μ1 and μ2 opioid receptor subtypes would lead to specific μ-opioid agonists that did not cause respiratory depression (Life Sci 1982;31:1303-6). The discovery of opioid receptor subtypes led to great pharmacology but no therapeutic breakthroughs.

Pasternak and colleagues also discovered that naloxonazine could antagonize morphine-induced analgesia but did not reverse morphine-induced respiratory depression (Pharmacol Biochem Behav 1986;24:1721-7). That’s not very useful! However, finding an antagonist that selectively reversed opioid-induced analgesia led to years of work trying to find its inverse: a drug that reversed opioid-induced respiratory depression without reversing analgesia. No such drug was ever found.

Biased opioids may be as close as we ever get to the holy grail of opioid pharmacology. However, the advances are not limited to opioids. As Porter-Stransky and Weinshenker note, “biased agonism complicates G-protein-coupled receptor activity, as different agonists at the same receptor can have opposing effects on physiology.” These authors note that other drugs, including oxytocin, cannabinoids, and psychostimulants, may have their normal responses altered with β-arrestin recruitment. This raises the possibility of the use of biased agonists as “potential therapeutics for addiction, analgesia, and other conditions.” Since the oxytocin receptor (OXTR) is also a class A G-protein-coupled receptor that recruits arrestins, a biased oxytocin receptor may have applicability in the treatment of autism, depression, and PTSD (J Biol Chem 2012;287:3617-29). On a lighter note, such a compound might be a useful addition to the drinking water supply, as the last two-plus years have shown that we could all use a little more empathy and compassion.