PZM21 is an experimental opioidanalgesic drug that is being researched for the treatment of pain.
It is claimed to be a functionally selectiveμ-opioid receptoragonist which produces μ-opioid receptor mediated G proteinsignaling, with potency and efficacy similar to morphine, but with less β-arrestin 2 recruitment . However, recent reports highlight that this might be due to its low intrinsic efficacy , 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. 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. 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.
^Gillis A, Gondin AB, Kliewer A, Sanchez J, Lim HD, Alamein C, et al. (March 2020). "Low intrinsic efficacy for G protein activation can explain the improved side effect profiles of new opioid agonists". Science Signaling. 13 (625): eaaz3140. doi:10.1126/scisignal.aaz3140. PMID32234959. S2CID214771721.