PZM21 explained

PZM21 is an experimental opioid analgesic drug that is being researched for the treatment of pain.^[1] It is claimed to be a functionally selective μ-opioid receptor agonist which produces μ-opioid receptor mediated G protein signaling, with potency and efficacy similar to morphine, but with less β-arrestin 2 recruitment.^[2] However, recent reports highlight that this might be due to its low intrinsic efficacy,^[3] rather than functional selectivity or 'G protein bias' as initially reported. In tests on mice, PZM21 was slightly less potent than morphine or TRV130 as an analgesic, but also had significantly reduced adverse effects, with less constipation than morphine, and very little respiratory depression, even at high doses.^[4] This research was described as a compelling example of how modern high-throughput screening techniques can be used to discover new chemotypes with specific activity profiles, even at targets such as the μ-opioid receptor which have already been thoroughly investigated.^[5] More recent research has suggested however that at higher doses, PZM21 is capable of producing classic opioid side effects such as respiratory depression and development of tolerance and may have only limited functional selectivity.^[6]

See also

• Cebranopadol
• DPI-3290
• AT-076
• AT-121
• SHR9352
• SR-17018
• TRV734

Notes and References

1. Kostic M . Biasing Opioid Receptors and Cholesterol as a Player in Developmental Biology . Cell Chemical Biology . 23 . 9 . 1039–1040 . September 2016 . 27662248 . 10.1016/j.chembiol.2016.09.007 . free .
2. Manglik A, Lin H, Aryal DK, McCorvy JD, Dengler D, Corder G, Levit A, Kling RC, Bernat V, Hübner H, Huang XP, Sassano MF, Giguère PM, Löber S, Scherrer G, Kobilka BK, Gmeiner P, Roth BL, Shoichet BK . 6 . Structure-based discovery of opioid analgesics with reduced side effects . Nature . 537 . 7619 . 185–190 . September 2016 . 27533032 . 5161585 . 10.1038/nature19112 . Peter . 2016Natur.537..185M . Brian K. . Grégory . Brian K. . Bryan L. .
3. Gillis A, Gondin AB, Kliewer A, Sanchez J, Lim HD, Alamein C, Manandhar P, Santiago M, Fritzwanker S, Schmiedel F, Katte TA, Reekie T, Grimsey NL, Kassiou M, Kellam B, Krasel C, Halls ML, Connor M, Lane JR, Schulz S, Christie MJ, Canals M . 6 . Low intrinsic efficacy for G protein activation can explain the improved side effect profiles of new opioid agonists . Science Signaling . 13 . 625 . eaaz3140 . March 2020 . 32234959 . 10.1126/scisignal.aaz3140 . 214771721 .
4. Manglik A, Lin H, Aryal DK, McCorvy JD, Dengler D, Corder G, Levit A, Kling RC, Bernat V, Hübner H, Huang XP, Sassano MF, Giguère PM, Löber S, Scherrer G, Kobilka BK, Gmeiner P, Roth BL, Shoichet BK . 6 . Structure-based discovery of opioid analgesics with reduced side effects . Nature . 537 . 7619 . 185–190 . September 2016 . 27533032 . 5161585 . 10.1038/nature19112 . Peter . 2016Natur.537..185M . Brian K. . Grégory . Brian K. . Bryan L. .
5. Kieffer BL . Drug discovery: Designing the ideal opioid . Nature . 537 . 7619 . 170–171 . September 2016 . 27533037 . 10.1038/nature19424 . free . 2016Natur.537..170K .
6. Hill R, Disney A, Conibear A, Sutcliffe K, Dewey W, Husbands S, Bailey C, Kelly E, Henderson G . 6 . The novel μ-opioid receptor agonist PZM21 depresses respiration and induces tolerance to antinociception . British Journal of Pharmacology . 175 . 13 . 2653–2661 . July 2018 . 29582414 . 6003631 . 10.1111/bph.14224 .