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Opioids Analgesics and Antagonists
Published in Sahab Uddin, Rashid Mamunur, Advances in Neuropharmacology, 2020
R. Rachana, Tanya Gupta, Saumya Yadav, Manisha Singh
According to recent studies, opioid-induced analgesia is a result of MOR signaling through the G protein, while the side effects, are conferred via β-arrestin pathway (Manglik et al., 2016). Some of these various new structure-based alternatives to morphine opioid analgesics are BU08028, PZM21, and NFEPP and so on. These compounds act only on the analgesics pathway and therefore, have shown minimal side effects like respiratory regression, sedation, constipation, addictiveness, and opioid dependence (Ding et al., 2016; Manglik et al., 2016; Chan et al., 2017). These compounds are still in trials and might become great alternatives to the conventional opioid drugs in future.
Preclinical discovery and development of oliceridine (Olinvyk®) for the treatment of post-operative pain
Published in Expert Opinion on Drug Discovery, 2022
Ammar A.H. Azzam, David G. Lambert
Addressing in vivo actions in a hot plate (antinociception) and whole body plethysmography (respiratory) assay oliceridine and PZM21 produced robust antinociceptive responses and respiratory depression (for PZM21 this is at odds with the original paper from Manglik et al. [15]. There were reported solubility issues with SR-17018 but there was an antinociceptive response and respiratory depression at achievable doses. Of more interest is the therapeutic window calculated from the respiratory depressant action at equi-antinociceptive doses. Olicerdine and PZM21 produced less respiratory depressant effects, a preclinical advantage over morphine and fentanyl, and we will address this for oliceridine below. There was an estimated advantage for SR-17018. Of note, buprenorphine was described as having the ‘safest profile.’ As noted, further work on constipation, tolerance, and physical addiction is warranted. Collectively, bias factors in vitro did not predict therapeutic window, rather this was predicted by intrinsic activity. This, therefore, questions the validity of bias ascription in general and for oliceridine specifically in the context of this current opinion article.
Current strategies toward safer mu opioid receptor drugs for pain management
Published in Expert Opinion on Therapeutic Targets, 2019
Aliza T. Ehrlich, Brigitte L. Kieffer, Emmanuel Darcq
An innovative drug discovery strategy is to use the solved crystal structural data of the drug target. Recent drug discovery efforts have used crystal structures of aminergic family GPCRs to computationally dock molecules, determining ligands with new scaffolds and nanomolar range potencies [49]. The inactive mouse MOR 2.8 Å crystal structure was determined in 2012 by X-Ray crystallography [50]. The binding pocket permits the ligand to bind deeply within a solvent-exposed space, distinct from the more commonly observed deeply buried binding pockets in other GPCRs. In a first structure-based MOR targeted campaign, over 3 million compounds were computationally docked against the inactive MOR structure to identify a novel chemical entity entirely distinct from known MOR agonists, which was further optimized to produce PZM21 [51]. This novel MOR opioid has unmatched selectivity, potency and biased G protein signaling that produces long-lasting analgesia with less unfavorable behavioral properties (respiratory depression, locomotor and reward) [51]. Additionally, PZM21 activation leads to low MOR internalization and undetectable β-arrestin 2 recruitment even in the presence of overexpressed GRK2 [51]. PZM21 encompasses a potential to be a safer pain killer however, a recent study has demonstrated that in their experimental conditions PZM21 could produce respiratory depression at the same level as morphine [52] suggesting that further research will be needed to uphold the high promise of this new opioid.