Mini Review

Dualism, Allosteric Modulation and Biased Signaling of Opioid Receptors: Future Therapeutic Potential

Antonio M González* and Alberto G Jubete

Service of Anesthesiology, Universitary Hospital Marqués de Valdecilla, Santander. Cantabria, Spain

Submission: August 05, 2021; Published: March 15, 2021

*Corresponding author: Dr Antonio M González, Service of Anesthesiology, Universitary Hospital Marqués de Valdecilla, Santander. Cantabria, Spain, Tel: +34 656826002

How to cite this article: Antonio M G, Alberto G J. Dualism, Allosteric Modulation and Biased Signaling of Opioid Receptors: Future Therapeutic Potential. J Anest & Inten care med. 2021; 11(2): 555808. DOI 10.19080/JAICM.2021.11.555808

Keypoints

• To know the molecular targets of action of opiate drugs.

• To check the different implications of allosteric modulation: PAMs, NAMs and SAMs

• To know the implications of biased signaling in modulating opiate-derived adverse effects.

• To know the property of the differential activation of the second messengers.

Mini Review

Opioid drugs remain as drugs of choice for the treatment of acute post-surgical pain, as well as for the treatment of chronic cancer pain [1]

Unfortunately, despite their high efficacy, they are not without adverse effects, such as nausea, constipation, drowsiness, respiratory depression, hyperalgesia, allodynia, tolerance, dependence and addition, which can produce, especially in forms of chronic treatment, a limitation on the life quality of the patient [2].

Their inadequate prescription has given rise to a true “opioid crisis” in some countries such as the US, where an estimated 115 deaths / day occur from opioid overdose, in what constitutes one of the worst mortality crises in its history [3], which has determined the need to search for new drugs with better therapeutic profiles for pain management, which is not without difficulties, since it is found: a) multiple receptors and neurotransmitters are involved in pain processing

b) multiplicity of responses produced by the simple activation of a receptor

c) the different intrinsic activities of the compounds, which can act as total agonists up to inverse agonists

.

d) presence of various fixation sites, specific (orthostatic) or non-specific (allosteric) and multiple intracellular effector mechanisms

In a very brief way, the opiate effects are mediated by the activation of the different receptors: mu (MOR), delta (DOR), kappa (KOR) and nociceptin (NOR). All belong to the class A G-protein-coupled receptor (GPCR) superfamily [4]. All GPCRs are integral membrane proteins with a common structure, configured by an extracellular N-terminal domain (with various N-glycosylation sites), seven transmembrane domains linked to an intracellular C-terminal domain, responsible of its interaction with heterotrimeric G proteins, and with various places for phosphorylation that may involve functional changes in the receptor. All receptors modulate both presynaptic and postsynaptic calcium channels, blocking ion flow, which is preferably related to reduced excitability or inhibition of neurotransmitter release.

Although the mu receptor (MOR) has been the main target for the formulation of analgesic drugs, all mu agonists have respiratory depression and dependence [5]. These side effects are reversed for MOR antagonist and are not observed in MORknockout models, showing that are mediated by the MOR.

In the current situation of opioid crisis, more attention has been paid to the other opioid receptors. They can also mediate analgesia and have some very interesting properties. Thus, delta agonists (DOR) have anxiolytic and antidepressant effects [6], and do not cause physical dependence, therefore they have a high margin against potential abuse. In the same sense, the activation of NOR seems to produce different effects depending on the exposure to exogenous opioid agonists, being able to block the analgesic response or reduce opiate tolerance.

Recent evidence shows that opioid receptors forms and can function as heterodimers [7] composed of different opioid receptors (eg DOR-MOR). Individual partners can traffic independently or as the heterodimer and acts like and allosteric regulator to increase the affinity of a ligand to the partner promoter. Consequently, a whole line of research has been developed aimed towards new drugs with duality of receivers, so that they can produce a mixture of effects that overcome the intrinsic limitations of each type of receptor.

One therapeutic approach has been the development of a bivalent ligands that consist of a MOR agonist (oxymorphone) and DOR antagonist (naltrindole) separated by different spacer lengths. These have shown analgesic activity with comparatively decreased rewarding effects, and diminished development of tolerance and dependence [8]. IBNtx-A is an agonist that act by binding the heterodimer MOR-NOR and showed potent analgesic effects in the absence of respiratory depression, constipation, rewarding effects or development of physical dependence [9].

We currently know that the conformational state of GPCRs (resting-active) is determined not only by the binding of the agonist at the specific (orthostatic) binding site but is also modulated by the binding of various ligands at other non-specific receptor sites (allosteric). These binding sites have the ability to bind different chemical elements with the capability to modulate the activity derived from binding of the agonist to the receptor, modifying its affinity, potency, and even efficacy [10].

We therefore have different allosteric modulators: positive allosteric modulators (PAMs) whose binding increases the activity of orthostatic ligands, negative allosteric modulators (NAMs) with the opposite effect, and silent allosteric modulators (SAMs) whose allosteric occupation it does not produce activity and behaves as an antagonist for both PAMs and NAMs.

Although theoretically the PAMs and NAMs would respectively increase / inhibit the affinity / efficacy of the orthostatic ligand without the ability to produce receptor activation “per se”, some compounds also appear to have intrinsic agonist activity, and are known as “agoPAMs”.

Allosteric ligands have several potential advantages over traditional orthosteric ligands as drugs. Because they do not bind to highly conserved orthosteric binding pockets, allosteric ligands can exhibit greater receptor selectivity [11]. Additionally, PAMs have key potential advantages over orthosteric agonist drugs: PAMs can increase the amplitude while maintaining the spatial and temporal fidelity, and the physiological regulation, of native signaling patterns –something that orthosteric agonist drugs cannot come close to doing.

Initially two opioids NAMs were discovered. Cannabidiol, a cannabinoid agonist was identified as a NAM of MOR and DOR due to its capacity to accelerate the dissociation of μ and δ-agonist [12]. Salvinorin A is a potent hallucinogenic κ-opioid receptor agonist that also inhibit the binding of DAMGO from MOR acting as negative allosteric modulator of the MOR [13].

More recently some PAMs and SAMs have been identified. BMS-986122 is a sulfonyl thiazolidine that potentiated the effects of DAMGO and endogenous agonist acting as PAM of the MOR and SAM of the DOR. BMS-986187 is a structural distinct PAM for DOR that also exhibits μ-PAM and κ-PAM activity over MOR and KOR receptors, respectively.

Another potential additional advantage of anesthetic modulating ligands may be the capability to introduce differential activation in the second messenger, facilitating preferential activation of one over the other, in what is called “biased agonism”. Thus, the same receptor can engage either G-proteindependent signaling or b-arrestin-dependent depending on the ligand bound. For the MOR, analgesic effects are proposed to occur through Gi/o-protein-depending signaling whereas respiratory depression and constipation are mediated through b-arrestin 2-related pathway. In the same way, KOR analgesic and antipruritic affects were ligated to Gi/o activation and dysphoric effects were associated to b-arrestin 2 activity.

The ultimate goal of this ability would be to preferentially activate the second messenger mechanism responsible for the beneficial effects of opioid activity without activating those responsible for the adverse effects.

In this sense, the use of MOR PAM ligands, such as oliceridine or PZM21 that prevent the activation of b-arrestin could potentiate beneficial effects at MOR level with less adverse effects. The preferential activation of the Gi/o protein-depending signaling may predict the therapeutic window for analgesia versus constipation and respiratory depression [14]. Currently, TVR 130 is a MOR Gi-biased agonist in clinical trials for the treatment of moderate to severe pain [15].

Similarly, the use of allosteric modulators at the DOR level could facilitate the achievement of antidepressant therapeutic effects, avoiding proconvulsant adverse effects; or at the KOR level, where the analgesic effects are limited by their dysphoric effects, being able to separate these dualities would be very important in order to limit the undesirable effects linked to the non-selective activation of opiate agonists.

Selective allosteric ligands for μ- and δ-opioid receptors have been described. These compounds bind to a site on the receptor distinct from the orthosteric site [16]. Occupation of this allosteric site leads to modulation of orthosteric ligand binding affinity and/ or efficacy [17].

Our next challenge will be to identify the structural determinants of the biased agonism in order to design drugs with better therapeutic windows [18].

References

1. Vallejo R, Barkin RL, Wang VC (2011) Pharmacology of opioids in the treatment of chronic pain syndromes. Pain Physician 14: E343–E360.
2. McNicol E, Horowicz-Mehler N, Fisk RA, Bennett K, Gialeli-Goudas M, et al. (2003) anagement of opioid side effects in cancer-related and chronic noncancer pain: a systematic review. J Pain 4(5): 231-256.
3. Volkow ND, McLellan AT (2016) Opioid Abuse in Chronic Pain -- Misconceptions and Mitigation Strategies. N Engl J Med 374(13): 1253-1263.
4. Shang Y, Filizola M (2015) Opioid receptors: Structural and mechanistic insights into pharmacology and signaling. Eur J Pharmacol 763(Pt B): 206-213.
5. Ossipov MH, Lai J, King T, Vanderah TW, Porreca F (2005) Underlying mechanisms of pronociceptive consequences of prolonged morphine exposure. Biopolymers 80(2-3): 319-324.
6. Jutkiewicz EM (2005) The Antidepressant -like Effects of Delta-Opioid Receptor Agonists. Mol Interv 6(3): 162-169.
7. Gomes I, Gupta A, Filipovska J, Szeto HH, Pintar JE, et al. (2004) A role for heterodimerization of mu and delta opiate receptors in enhancing morphine analgesia. Proc Natl Acad Sci USA 101(14): 5135–5139.
8. Lenard NR, Daniels DJ, Portoghese PS, Roerig SC (2007) Absence of conditioned place preference or reinstatement with bivalent ligands containing mu-opioid receptor agonist and delta-opioid receptor antagonist pharmacophores. Eur J Pharmacol 566(1-3): 75–82.
9. Valentino RJ, Volkow ND (2018) Untangling the complexity of opioid receptor function. Neuropsychopharmacology 43(13): 2514-2520.
10. Livingston KE, Traynor JR (2018) Allostery at opioid receptors: modulation with small molecule ligands. Br J Pharmacol 175(14): 2846-2856.
11. Burford NT, Traynor JR, Alt A (2015) Positive allosteric modulators of the mu-opioid receptor: a novel approach for future pain medications. Br J Pharmacol 172(2): 277–286.
12. Kathmann M, Flau K, Redmer A, Trankle C, Schlicker E (2006) Cannabidiol is an allosteric modulator at mu- and delta-opioid receptors. Naunyn-Schmiedeberg's Arch Pharmacol 372(5): 354-361.
13. Rothman RB, Murphy DL, Xu H, Godin JA, Dersch CM, et al. (2007) Salvinorin A: allosteric interactions at the mu-opioid receptor. J Pharmacol Exp Ther 320(2): 801-810.
14. Bohn LM, Gainetdinov RR, Lin FT, Lefkowitz RJ, Caron MG (2000) Mu-opioid receptor desensitización by beta-arrestin-2 determines morphine but not dependence. Nature 408(6813): 720-723.
15. Miyano K, Manabe S, Komatsu A, Fujii Y, Mizobuchi Y, et al. (2021) The G Protein Signal-Biased Compound TRV130; Structures, Its Site of Action and Clinical Studies. Curr Top Med Chem 20(31): 2822-2829.
16. Remesic M, Hruby BJ, Porreca F, Lee YS (2017) Recent advances in the realm of allosteric modulators for opioid receptors for the future therapeutics. ACS Chem Neurosci 8(6):1147-1158.
17. Bartuzi D, Kedzierska E, Kaczor A, Schmidhammer H, Matosiuk D (2020) Novel Positive Allosteric Modulators of µ Opioid Receptor-Insight from In Silico and In Vivo Studies. Int J Mol Sci 21(22): 8463-8478.
18. Bartuzi D, Wróbel TM, Kaczor A, Matosiuk D (2021) Tuning Down the Pain – An Overview of Allosteric Modulation of Opioid Receptors: Mechanisms of Modulation, Allosteric Sites, Modulator Syntheses. Curr Top Med Chem 20(31): 2852-2865.