Unlocking further potential of current clinical drugs with biased agonists and allosteric modulators

By Kilian Robinson

GPCR’s are transmembrane proteins that are involved in a multitude of physiological processes and therefore have been attractive targets for drugs in recent years. In fact, approximately 34% of drugs passed by the FDA work to target GPCR’s and these include some of the most important clinically used drugs, such as antihistamines and opioids.1 Unfortunately, the efficacy of these drugs is hindered by their tendency to produce adverse effects, to the extent that the benefits are sometimes shadowed by them. To solve this problem, we will be discussing the role of biased agonists and allosteric modulators and how these molecules can be used to enhance the effects of GPCR drugs whilst simultaneously reducing the adverse ones.

An example of a GPCR is the μ-opioid receptor (MOPr) which responds to the opioid ligand fentanyl. When fentanyl is administered, it binds to the orthosteric pocket within the MOPr and causes a shift in its confirmation. This change in confirmation activates a cascade reaction by activating a G-protein which eventually results in antinociception. However, the MOPr does not just control one signaling pathway, it is flexible and can also activate a β-arrestin pathway which can produce significant respiratory depression.2 In fact, fentanyl prioritises this pathway over the pain relief pathway, which limits the use of fentanyl in its effort to relieve pain. 

In recent research to resolve the issue of adverse effects causes by the antagonistic pathway, researchers have manufactured synthetic opioid ligands designed to preferentially select the antinociception signaling pathway to enhance the pain relief properties created when taking opioids. These ligands are known as biased ligands and researchers have synthesised some promising data, especially with the ligand SR-17018 shown in the figure below.

Figure 1 The MOPr is a GPCR which responds to opioid ligands, with its main function in medicine being stimulating pain relief. Fentanyl binds to the orthosteric binding pocket within the MOPr, which stimulates antinociception but preferentially selects the β-arrestin pathway resulting in respiratory depression limiting its use, clinically. However, SR-17018 carries out the opposite, making synthetic opioid ligands a much more attractive potential option in future medicine.2 

These biased ligands are incredibly important to modern medicine. There are many drugs just like fentanyl which cause adverse effects and therefore we need to extend the pharmacological efficacy and safety of our current clinical drugs and biased ligands may just achieve that. Hence, further research into these may allow us to re-invent drugs used at present to achieve a much higher level of treatment.

In addition to biased agonism, biased allosteric modulators (BAMs) are an emerging class of GPCR drug molecules that show promise in our effort to improve drug treatment. BAMs are similar to biased ligands in that they interact with specific motifs outside the orthosteric binding pocket to exert effects that modulate pathway selection1. These are also significant as they could potentially provide us with an even greater degree of control and thus improve treatment of physiological diseases.

Biased allosteric modulation can be exemplified in the Neurotensin receptor 1 (NTSR1) which is utilized in the attenuation of drug addiction. Evidence suggests that the dysregulation of central dopaminergic neurotransmission, through dopamine receptor D2 especially, can contribute to the abuse of opioids and many other drugs3,4,5. Neurotensin (an NTSR1 ligand) is used to attenuate these addictive behaviours but of course, like fentanyl, it does not come without its disadvantages. The G-protein pathway in this GPCR can stimulate things such as hypothermia, hypotension, and motor impairment, as described in Figure 2. In treatment, we can use SBI-553 (a biased allosteric modulator) to bind with or without neurotensin to prioritise the β-arrestin pathway thus yielding a reduction in addictive behaviour.6

Figure 2 – The GPCR NTSR1 responds to neurotensin (NT) and can be used to bias to the β-arrestin pathway yielding the attenuation of addictive behaviour. An experiment detailed below briefly details how cocaine administration led to a hypothermic and motor impaired rat when SBI-553 was not administered, conversely, the rat that did obtain SBI-553, had no issues.6

In the data below, we can see that the Biased agonistic modulator can act like a biased agonist, eliminating a certain pathway to bias NTSR1 to the β-arrestin pathway, but when paired with neurotensin, you can increase and decrease concentrations to modulate how much of each pathway you require, instead of completely removing a pathway. This has important implications as you may need to maintain hormone rhythms to allow you to enhance the effect of certain pathways without it affecting other physiological processes quite so much. Or it may be that the other pathway is valuable, just to a lesser extent4. These modulators allow us to manipulate, enhance and accurately change pharmacological effects we yield from drugs and these properties can be used to advance the therapeutic options we have.

Figure 3 –  A figure displaying dose response curves of maximum efficacy (Emax) against log concentration of neurotensin (NTS). (C) With the NTS alone, both pathways are equally activated, which would attenuate some addictive behaviours, but still with adverse effects as seen in the rats. (D) With SBI-553 (BAM) alone, only β-arrestin is stimulated and thus only producing beneficial effects (like in figure 2). (E) Finally, with both the ligand and the BAM present, you can modulate the level of activity you require, depending on the concentration of SBI-553 (indicated by increasing level of blue saturation)1

Over the last decade, many of the new drugs being produced by pharmaceutical companies have failed, with greater than 90% of agents not completing Phase 1 clinical trials due to efficacy and safety5. Clearly, finding and producing new medicines is becoming much more difficult and hence we must investigate other ways of producing our desired pharmacological effects. Biased agonists and biased allosteric modulators solve some of the problems we have with drugs that have adverse effects and offer the opportunity to upgrade and improve our current drug library, to the extent that they can almost be considered completely new drugs. Of course, there are many issues with these drugs such as quantifying bias, describing ligand profiles and more intricate interactions. However, medicine must take the next step forward so that we can continue to provide the best possible treatment for patients in need.


  1. Hauser, A.S., Attwood, M.M., Rask-Andersen, M., Schiöth, H.B. & Gloriam, D.E. 2017, “Trends in GPCR drug discovery: new agents, targets and indications”, Nature Reviews Drug Discovery, vol. 16, no. 12, pp. 829-842. Available at: https://www.nature.com/articles/nrd.2017.178 [Accessed 09/10/21]
  2. Slosky, L M., Caron, M. G., Barak, L. S. (2020) “Biased Allosteric Modulators: New Frontiers in GPCR Drug Discovery”, Trends in Pharmacological Sciences. Apr;42(4):283-299. doi: 10.1016/j.tips.2020.12.005. Epub 2021 Feb 10. PMID: 33581873. [Accessed 09/10/21]
  3. Baicy K, London E. D. (2007) “Corticolimbic dysregulation and chronic methamphetamine abuse”. Addiction.  Apr;102 Suppl 1:5-15. doi: 10.1111/j.1360-0443.2006.01777.x. PMID: 17493049.
  4. Groman SM, Lee B, Seu E, James AS, Feiler K, Mandelkern MA, London ED, Jentsch JD. (2012) “Dysregulation of D₂-mediated dopamine transmission in monkeys after chronic escalating methamphetamine exposure”. J Neurosci.  Apr 25;32(17):5843-52. doi: 10.1523/JNEUROSCI.0029-12.2012. PMID: 22539846; PMCID: PMC3353813.
  5. Parsegian, Aram, and Ronald E See. (2014)  “Dysregulation of dopamine and glutamate release in the prefrontal cortex and nucleus accumbens following methamphetamine self-administration and during reinstatement in rats.” Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology vol. 39,4 : 811-22. doi:10.1038/npp.2013.231
  6. Slosky, Lauren M et al. “β-Arrestin-Biased Allosteric Modulator of NTSR1 Selectively Attenuates Addictive Behaviors.” Cell vol. 181,6 (2020): 1364-1379.e14. doi:10.1016/j.cell.2020.04.053
  7. Stanczyk, M.A. & Kandasamy, R. 2018, “Biased agonism: the quest for the analgesic holy grail”, PAIN Reports, vol. 3, no. 3, pp. e650. Available at: https://journals.lww.com/painrpts/Fulltext/2018/06000/Biased_agonism__the_quest_for_the_analgesic_holy.1.aspx [Accessed 09/10/21]
  8. Dowden, H., Munro, J. (2019 “Trends in clinical success rates and therapeutic focus”. Nature. Available at: Trends in clinical success rates and therapeutic focus (nature.com) [Accessed 09/10/21]

Leave a Reply


WordPress.com Logo


Twitter picture


Facebook photo


Connecting to %s