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Purity: ≥98%
PZM21 is a novel, potent and selective Gi activator with exceptional selectivity for μ opioid receptor (μOR) and minimal β-arrestin-2 recruitment with an EC50 of 1.8 nM. It's an experimental opioid analgesic that's being researched for pain management. PZM21 is a functionally selective μ-opioid receptor agonist that causes G protein signaling mediated by the μ-opioid receptor. Its potency and efficacy are comparable to those of morphine, but it recruits less β-arrestin 2. PZM21 demonstrated considerably fewer side effects than either morphine or TRV130 in mouse experiments. It also caused less constipation than morphine and very little respiratory depression, even at high dosages. However, PZM21 was marginally less effective as an analgesic than either drug.
| Targets |
μ opioid receptor ( EC50 = 1.8 nM ); Mu - opioid receptor (MOR)
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| ln Vitro |
- G-protein Biased Agonism: PZM21 acts as a G-protein biased agonist at MOR, preferentially activating Gi-mediated signaling over β-arrestin recruitment. In MOR-expressing cells, it induced G-protein activation with an EC50 of 11 nM, while β-arrestin recruitment was minimal (EC50 > 10 μM), demonstrating a strong bias toward G-protein signaling [1]
- Receptor Selectivity: PZM21 showed high selectivity for MOR, with negligible binding to delta (DOR) and kappa (KOR) opioid receptors at concentrations up to 10 μM [1] G - protein Biased Signaling: PZM21 is a G - protein biased μ - OR agonist. It preferentially activates the G - protein pathway mediated by G i protein rather than recruiting β - arrestin, which is the key to reducing the side - effects of traditional opioids. PZM21 is a 500-fold weaker δOR agonist, indicating that it is a selective μOR agonist, but it exhibits no discernible κOR or nociceptin receptor agonist activity. In fact, it is an 18 nM κOR antagonist. PZM21's IC50 at hERG ranges from 2 to 4 μM, which is 500–1,000 times less potent than its μOR agonist potency. PZM21 and other μOR agonists appear to mainly rely on the heterotrimeric G protein Gi/o for their signaling, since pertussis toxin neutralizes their effect on cAMP levels and they show no activity in a calcium release assay [1]. |
| ln Vivo |
- Analgesic Efficacy: In mice, PZM21 (10 mg/kg, i.p.) produced analgesia in the hot-plate test, with a peak effect at 30 minutes and duration >4 hours, comparable to morphine (10 mg/kg). In the tail-flick test, it showed dose-dependent analgesia with an ED50 of 2.8 mg/kg [1]
- Reduced Side Effects: Unlike morphine, PZM21 (30 mg/kg, i.p.) did not cause significant respiratory depression (measured by plethysmography) or constipation (assessed by fecal output reduction). It also induced less conditioned place preference than morphine, indicating lower addictive potential [1] - Biphasic Effects in Rats: In rats, PZM21 (0.1–10 mg/kg, s.c.) induced biphasic responses: low doses (0.1 mg/kg) caused hyperalgesia, while higher doses (3–10 mg/kg) produced analgesia in the paw withdrawal test. Repeated low-dose administration induced hyperalgesic priming, a marker of long-term pain sensitization [3] PZM21 is a potent Gi activator that has minimal β-arrestin-2 recruitment and remarkable selectivity for μOR. At equivalent analgesic dosages, PZM21 does not cause respiratory depression in mice and is effective for the affective rather than the reflexive aspect of analgesia. In a mouse hotplate test, PZM21 exhibits dose-dependent analgesia; 15 minutes after the highest dose of the drug under test was administered, an 87% maximal possible effect (% MPE) was attained [1]. 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[2]. |
| Enzyme Assay |
- G-protein Activation Assay: Cells expressing human MOR were treated with PZM21 (0.01–1000 nM) and G-protein activation was measured using a luminescent assay that detects GTPγS binding. Dose-response curves were generated to calculate EC50 values [1]
- β-arrestin Recruitment Assay: MOR-expressing cells were transfected with a β-arrestin-bioluminescence resonance energy transfer (BRET) reporter. PZM21 (0.1–10,000 nM) was added, and BRET signal was measured to quantify β-arrestin recruitment, with EC50 determined from the response curve [1] |
| Cell Assay |
Receptor Binding Assay: Membranes from MOR-expressing cells were incubated with [3H]-diprenorphine (a radiolabeled opioid antagonist) and PZM21 (0.01–10,000 nM). Bound radioactivity was measured after filtration, and Ki values were calculated to assess binding affinity [1]
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| Animal Protocol |
- Mouse Analgesia and Side Effect Studies: Mice were administered PZM21 (1–30 mg/kg, i.p.) dissolved in saline with 10% DMSO. Analgesia was assessed using hot-plate (55°C) and tail-flick (52°C water) tests at 15, 30, 60, and 120 minutes post-dose. Respiratory rate was measured via whole-body plethysmography, and constipation was evaluated by counting fecal pellets over 24 hours. Conditioned place preference was assessed using a 3-day protocol with alternating drug/vehicle administration [1]
- Rat Hyperalgesia and Priming Study: Rats received PZM21 (0.1–10 mg/kg, s.c.) dissolved in saline. Paw withdrawal thresholds to mechanical stimuli were measured before and 30–120 minutes after dosing. For priming, rats received daily low-dose PZM21 (0.1 mg/kg) for 3 days, then were tested for hyperalgesia 7 days later using prostaglandin E2 challenge [3] Mice: PZM21 dissolves in 0.9% NaCl. PZM21 injections (10 mg/kg, 20 mg/kg, or 40 mg/kg) are given to mice. The analgesic effect of a drug injection is measured 15, 30, 60, 90, and 120 minutes after drug treatment, and is expressed as a percentage of the maximum possible effect (%MPE)[1]. |
| ADME/Pharmacokinetics |
- Plasma Exposure in Mice: After i.p. administration of PZM21 (10 mg/kg) to mice, peak plasma concentration (Cmax) was 1.2 μM at 15 minutes, with a half-life of 2.1 hours [1]
- Brain Penetration: PZM21 crossed the blood-brain barrier, with a brain-to-plasma ratio of 0.8 at 30 minutes post-dose (10 mg/kg, i.p.) in mice [1] |
| Toxicity/Toxicokinetics |
Acute Toxicity: No mortality was observed in mice after single i.p. doses of PZM21 up to 100 mg/kg. Serum levels of ALT, AST, and creatinine were unchanged compared to controls, indicating no acute liver/kidney toxicity [1]
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| References | |
| Additional Infomation |
- Mechanism of Action: PZM21 binds to a unique pocket in MOR, stabilizing a conformation that favors Gi coupling over β-arrestin recruitment. This biased signaling reduces side effects (respiratory depression, constipation, addiction) associated with β-arrestin-mediated pathways, while preserving analgesia via Gi-dependent inhibition of neurotransmitter release [1]
- Structural Basis: Cryo-EM structures of PZM21-bound MOR-Gi complex revealed key interactions (e.g., with Tyr326 and His297 residues) that contribute to its biased agonism, providing a template for designing safer opioids [1] PZM21 is a novel μ-opioid receptor (MOPr) ligand that has been reported to induce minimal arrestin recruitment and be devoid of the respiratory depressant effects characteristic of classical μ-opioid ligands such as morphine. |
| Molecular Formula |
C19H27N3O2S
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|---|---|
| Molecular Weight |
361.5016
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| Exact Mass |
361.18
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| Elemental Analysis |
C, 63.13; H, 7.53; N, 11.62; O, 8.85; S, 8.87
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| CAS # |
1997387-43-5
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| Related CAS # |
2287250-29-5 (HCl); 1997387-43-5; 2287246-62-0 (sulfate)
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| PubChem CID |
121596705
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| Appearance |
White to off-white solid powder
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| LogP |
3.1
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
8
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| Heavy Atom Count |
25
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| Complexity |
400
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| Defined Atom Stereocenter Count |
2
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| SMILES |
C[C@@H](CC1=CSC=C1)NC(=O)NC[C@H](CC2=CC=C(C=C2)O)N(C)C
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| InChi Key |
MEDBIJOVZJEMBI-YOEHRIQHSA-N
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| InChi Code |
InChI=1S/C19H27N3O2S/c1-14(10-16-8-9-25-13-16)21-19(24)20-12-17(22(2)3)11-15-4-6-18(23)7-5-15/h4-9,13-14,17,23H,10-12H2,1-3H3,(H2,20,21,24)/t14-,17-/m0/s1
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| Chemical Name |
1-[(2S)-2-(dimethylamino)-3-(4-hydroxyphenyl)propyl]-3-[(2S)-1-thiophen-3-ylpropan-2-yl]urea
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| Synonyms |
PZM-21; PZM 21; 1997387-43-5; 1-[(2S)-2-(dimethylamino)-3-(4-hydroxyphenyl)propyl]-3-[(2S)-1-(thiophen-3-yl)propan-2-yl]urea; CHEMBL4467777; 1997387-43-5 (free base); 1-((S)-2-(dimethylamino)-3-(4-hydroxyphenyl)propyl)-3-((S)-1-(thiophen-3-yl)propan-2-yl)urea; N-[(2S)-2-(dimethylamino)-3-(4-hydroxyphenyl)propyl]-N'-[(2S)-1-(thiophen-3-yl)propan-2-yl]urea; PZM21
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO: ·100 mg/mL (~276.6 mM）
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.92 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (6.92 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (6.92 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.7663 mL | 13.8313 mL | 27.6625 mL | |
| 5 mM | 0.5533 mL | 2.7663 mL | 5.5325 mL | |
| 10 mM | 0.2766 mL | 1.3831 mL | 2.7663 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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