The Science-Du Yang team collaborated to develop non-opioid-free analgesics that target adrenergic receptors

Written by Binghao Zhang

Editor-in-charge - Wang Sizhen

Editor—Summer Leaf

The pandemic of pain and opioid addiction has highlighted the need for new non-opioid treatments for pain (Figure 1).

。 Many non-opioid receptors are involved in pain processing (nociceptive sensing), but only a few of them are therapeutic and proven analgesic targets
.
α 2A-adrenergic receptors (α_2AAR) are one Class A G-protein coupled receptors, whose activation in the central nervous system has a pain-relieving effect [1,2].

。 Drugs known to act α _2AAR, such as the imidazoles clonidine (clonidine) and dexmedetomidine (dexmedetomidine), has an analgesic effect[3].

Unfortunately, they also have a strong sedative effect; This sedative effect is important for the primary indications of these drugs, but limits their widespread use
as analgesics in hospitals.
Since α_2AAR can bind to a variety of downstream signaling proteins (such as G proteins, inhibitory protein arrestin, etc.
), This produces different physiological effects (eg, analgesia, sedative) [1].

Therefore, the development of a new agonist that is structurally different from traditional imidazoles such as clonidine and dexmedetomidine, and that selectively (biasedly) activates specific signaling pathways downstream, may eliminate or reduce its sedative effect and thus be used
as a non-opioid analgesic.

Figure 1 Opioid analgesic abuse crisis

(Source: https://avanospainmanagement.
com/posts/reducing-postoperative-opioids/).

Professor Du Yang's team, Hong Kong Chinese University (Shenzhen) School of Medicine/Kobilka Institute for Innovative Drug Development, and Professor Peter Gmeiner's team at the University of Erlangen-Nuremberg and Brian of the University of California, San Francisco Professor Shoichet's team and other common communications were published in the international leading scientific journal Science (IF=63.
71) entitled " Structure-based discovery of nonopioid analgesics acting through the α _{2A-adrenergic} receptor"
.
Jun Xu, postdoctoral fellow at Stanford University School of Medicine and former research assistant at the Kobilka Institute, Elissa Fink, PhD student at the University of California, San Francisco, and Dr.
Harald of the University of Erlangen-Nuremberg Hubner et al.
tied for first author
.
The work reported the development
of non-opioid-free analgesics targeting α 2A adrenergic receptors based on structural guidance.
(Further reading: The latest research results of Du Yang's team can be found in the "Logical Neuroscience" report (click to read): Nat Commun.
) —Du Yang's team in revealing the activation and allosteric regulation mechanism of human orphan receptor GPR88).

Based on the resolved cryo-EM structure of α_2A adrenergic receptors, this study uses leading molecular docking technology, medicinal chemical modification, structure-assisted design, animal experiments and other comprehensive means to obtain drug candidates with strong analgesic effects in animal
experiments.
This research strategy has also achieved some successful work in the past and represents the future direction of drug discovery based on GPCR structure [4].

Specifically, the authors screened 17 ligands α_2AAR from 301 million virtual molecules through molecular docking, with affinities as low as possible 12 nM, many of which are partial agonists and biased towards the_Gi and G_o signaling pathways
.
The researchers analyzed the structure of two ligands, the α_2AAR complex, by single-molecule cryo-EM, confirmed the prediction of molecular docking, and used this as a template to further optimize the ligand structure
.
' 9087 (initially screened agonist, median effective concentration (_EC50) 52 nM) and its two analogues, '7075 and PS75 (EC ₅₀ 4.
1 and 4.
8 nM, respectively), Analgesic effects were shown in several in vivo pain models without sedative and off-target effects (Figure 2).

These newly discovered agonists exhibit abundant druggable potential and exhibit advantages
over drug dependence (compared to opioids) and sedation (compared to imidazoles dexmedetomidine, etc.
).

Fig.
2 Development process of non-addictive painkillers targeting adrenergic receptors

(Source: Fink EA, et al.
) , Science, 2022）

The work revealed three key findings
.
First, effective agonists can be screened directly from large databases and can be independent
of known agonists.
Molecular docking can identify molecules with in vitro activity and make them active in vivo through structural activity optimization
.
Although direct detection of an effective agonist is rare, direct hits of an effective ligand in this experiment do indicate the advantages of a large virtual screening library, especially the efficacy
of a different chemotype from a known ligand.
Second, although the '9087 and its analogues '7075 and PS75' are not biased towards the Gi/o/z pathway β suppress protein pathway activity, but was not designed with functional selectivity as the design criterion, possibly because of their new chemotype
.
Although similar situations often occur in other studies, the logic that uncharacterized chemical forms cause new signaling pathways needs to be studied
more.
Third, '9087 and its analogues '7075, PS75 do not cause sedation or dyskinesia at analgesic doses, which has a wide range of application prospects and has been proven α_{2A AR} agonists can be differentiated
according to two effects.

Fig.
3 Analgesic effect in mouse neuralgia models of the new agonists '9087 and PS75

(Source: Fink EA, et al.
) , Science, 2022）