In vitro: PZM21 has no detectable κOR or nociceptin receptor agonist activity-it is actually an 18 nM κOR antagonist-while it is a 500-fold weaker δOR agonist, making it a selective μOR agonist. At hERG, PZM21 has an IC50 of between 2 and 4 μM, 500- to 1,000-fold weaker than its potency as a μOR agonist. Signalling by PZM21 and other μOR agonists appears to be mediated primarily by the heterotrimeric G protein Gi/o, as its effect on cAMP levels is eliminated by pertussis toxin and no activity is observed in a calcium release assay. In vivo: PZM21 is a potent Gi activator with exceptional selectivity for μOR and minimal β-arrestin-2 recruitment. Unlike morphine, PZM21 is more efficacious for the affective component of analgesia versus the reflexive component and is devoid of both respiratory depression and morphine-like reinforcing activity in mice at equi-analgesic doses. PZM21 displays dose-dependent analgesia in a mouse hotplate assay, with a per cent maximal possible effect (% MPE) of 87% reached 15 min after administration of the highest dose of drug tested. PZM21 has a long-lasting analgesic effect on CNS mediated-pain responses, but does not cause respiratory depression and constipation, two key side effects of opioid agonists. PZM21 do not exhibit the type of biomarker responses, such as hyperlocomotion or conditioned place preference response, that are observed when morphine and other opioids are used and are associated with reinforcement and addiction.
|Cell lines||HEK-293T cells|
|Preparation method||Determination of functional activity of PZM21-29 for SAR studies was performed using a BRET-based cAMP accumulation assay50.|
|Incubation time||24 h|
|Animal models||Adult male C57BL/6J|
|Formulation||0.9% sodium chloride|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Solubility||10mM in DMSO|
G-Protein-Coupled Receptors: Sustained Signaling via Intracellular Megaplexes and Pathway-Specific Drugs.
Link A, et al. Angew Chem Int Ed Engl. 2016 Dec 23;55(52):15962-15964. PMID: 27775210.
Structure-based discovery of opioid analgesics with reduced side effects.
Manglik A, et al. Nature. 2016 Sep 8;537(7619):185-190. PMID: 27533032.
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