ZL006-05
ZL006-05 is an orally active, brain-penetrant nNOS–PSD-95 and α2-containing GABAA dual-target inhibitor. ZL006-05 blocks the nNOS-PSD-95 protein-protein interaction and selectively potentiatesα2-containing GABAA receptors. ZL006-05 attenuates central sensitization and strengthens inhibitory GABAergic synaptic transmission. ZL006-05 can be used for the study of neuropathic pain, cancer pain, chemotherapy-induced peripheral neuropathic pain, ischemic stroke, poststroke depression and anxiety.
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- CAS No.: 2486316-20-3
- Formule: C24H27Cl2NO4
- Masse moléculaire:464.38
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Activité biologique
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Activité biologique
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nNOS |
GABAA receptor |
PSD-95 |
ZL006-05 (0-100 μM) potentiates GABA-evoked currents in lamina II neurons of the spinal dorsal horn; 1, 10 and 100 μM increase GABA-evoked current amplitudes by 1.42-fold, 1.71-fold and 1.68-fold, respectively[1].
ZL006-05 (10 μM) increases Isoguvacine hydrochloride (HY-100810) -evoked GABAA receptor currents in lamina II neurons by 1.57-fold, and shifts the Isoguvacine concentration-response curve leftward by reducing the EC50 from 38.22 μM to 5.12 μM[1].
ZL006-05 (10 μM) increases Isoguvacine-evoked currents in anterior cingulate cortex neurons by 1.53-fold [1].
ZL006-05 (0.1 nM-10 μM; acute co-perfusion with GABA) selectively potentiates GABA-evoked currents in HEK293 cells expressing α2β3γ2 GABAA receptors, while showing no obvious potentiation of α1β2γ2 GABAA receptors[2].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
| Species | Dose | Route | Note | T1/2 | Tmax | MRT0-t | MRT0-inf | CL | Vss | Cmax | AUC0-t | AUC0-inf |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Rat[3] | 2 mg/kg | i.v. | plasma | 2.78 h | 0.08 h | 0.46 h | 0.597 h | 683 mL/h/kg | 408 mL/kg | 6947 ng/mL | 2900 ng·h/mL | 2930 ng·h/mL |
| Rat[3] | 2 mg/kg | i.v. | brain | 19.89 h | 0.08 h | 11.46 h | 27.08 h | 1431 mL/h/kg | 38749 mL/kg | 104 ng/mL | 936 ng·h/mL | 1398 ng·h/mL |
ZL006-05 (0.4-4 mg/kg; i.v.; once daily; for 8 consecutive days starting on day 7 after RM-1 inoculation) dose-dependently reduces RM-1-induced mechanical allodynia, heat hyperalgesia, cold hyperalgesia and spontaneous pain behaviors during the maintenance period of bone cancer pain[1].
ZL006-05 (10 mg/kg; i.v.; once daily; for 7 consecutive days starting on day 9 after the first Paclitaxel (HY-B0015) injection) reduces Paclitaxel (HY-B0015)-induced bilateral mechanical allodynia, heat hyperalgesia and cold hyperalgesia in chemotherapy-induced peripheral neuropathic pain mouse model, reduces Paclitaxel-induced p-ERK1/2 and GFAP upregulation in the lumbar dorsal horn [1].
ZL006-05 (60 mg/kg/day; i.g.; for 11 consecutive days) reduces SNL-induced mechanical hyperalgesia in rats without analgesic tolerance[2].
ZL006-05 (60 mg/kg/day; i.g.; for 28 consecutive days) maintains long-term antinociceptive activity in Spinal Nerve Ligation (SNL) -induced neuropathic pain mice, whereas pregabalin shows severe analgesic tolerance under the same treatment duration[2].
ZL006-05 (0.3 mg/d; intrathecal osmotic pump infusion; for 11 days) increases mIPSC amplitude in lamina I excitatory neurons of the spinal dorsal horn after chronic intrathecal infusion, without affecting mEPSCs[2].
ZL006-05 (6 mg/kg for single intravenous injection or 90 mg/kg for single intragastric administration) shows no detectable free ZL006 or (+)-borneol in blood, with the parent compound as the dominant detected form[2].
ZL006-05 (0.5-4 mg/kg; i.v.; 60 min after reperfusion) dose-dependently reduces infarct volume and neurological score at 48 h after tMCAO in male and female rats, with an effective dose of 1 mg/kg[3].
ZL006-05 (2 mg/kg; i.v.; 60 min after reperfusion) reduces infarct volume, foot faults and neurological score on day 7 after tMCAO in male rats[3].
ZL006-05 (2 mg/kg; i.v.; at 2, 26 h after ischemia) improves motor function and reduces infarct volume on day 7 after photothrombotic stroke in mice[3].
ZL006-05 (2 mg/kg; i.v.; first dose at 6 or 12 h after ischemia and second dose 24 h after the first dose) improves sensorimotor function and reduces infarct volume on day 7 after photothrombotic stroke in rats[3].
ZL006-05 (2 mg/kg/day; i.v.; for 3 or 7 consecutive days after ischemia) improves long-term neurological deficit, sensorimotor function and spatial learning after photothrombotic stroke or tMCAO in rats[3].
ZL006-05 (2 mg/kg; i.v.; administered 60 min after reperfusion) reduces tPA-induced haemorrhagic transformation and deterioration of brain injury after ischemic stroke[3].
ZL006-05 (2 mg/kg; i.v.; behavioral tests at 60 min after injection) produces fast-onset anxiolytic-like and antidepressant-like effects in mice[3].
ZL006-05 (1, 2 mg/kg; i.v.; single administration after 28-day UCMS exposure) reverses UCMS-induced anxiety-related and depression-related behaviors at 60 min after injection, with significant activity at 2 mg/kg[3].
ZL006-05 (2 mg/kg/day; i.v.; for 7 consecutive days after stroke) prevents tMCAO-induced anxiety-related and depression-related behavioral changes in mice[3].
ZL006-05 (2 mg/kg; i.v.; single injection at 60 min after tMCAO reperfusion) in mice, reduces stroke-induced nNOS-PSD-95 interaction in the peri-infarct cortex and increases miniature inhibitory postsynaptic current amplitude, indicating enhanced inhibitory synaptic transmission[3].
ZL006-05 (10-40 mg/kg; single injection or repeated intravenous dosing for 28 consecutive days) in rats, exhibits dose-dependent rises in systemic exposure parameters (Cmax and AUC), with no gender disparity or drug accumulation detected, and shows a high safety profile[3].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:RM-1-induced metastatic bone cancer pain 8-week-old male C57BL/6 mice model[1]
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Dosage:4 mg/kg
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Administration:Intravenous injection (i.v.); 30 min after RM-1 inoculation and then once daily for 6 days
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Result:Abolished RM-1-induced mechanical allodynia, heat hyperalgesia and cold hyperalgesia on the ipsilateral side.
Reduced spontaneous pain behaviors, including guarding duration and flinching number.
Showed stronger antinociceptive activity than ZL005 or ZL006 at the same dose.
Did not alter basal paw withdrawal responses or locomotor function.
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Animal Model:RM-1-induced metastatic bone cancer pain 8-week-old male C57BL/6 mice model maintenance phase[1]
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Dosage:0.4, 2, 4 mg/kg
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Administration:Intravenous injection (i.v.); once daily; for 8 consecutive days starting on day 7 after RM-1 inoculation
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Result:Reduced RM-1-induced mechanical allodynia, heat hyperalgesia, cold hyperalgesia and spontaneous pain in a dose-dependent manner.
At 4 mg/kg on day 14, reduced paw withdrawal frequencies to 0.07 g and 0.4 g von Frey filaments by 62% and 50%, respectively.
At 4 mg/kg on day 14, increased paw withdrawal latencies to heat and cold stimuli by 1.58-fold and 1.39-fold, respectively.
At 4 mg/kg on day 14, reduced guarding duration and flinching number by 78% and 86%, respectively.
Did not alter basal responses on the contralateral hind paw.
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Animal Model:8-week-old male C57BL/6 mice RM-1-induced dorsal horn neuronal and astrocyte hyperactivity model[1]
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Dosage:4 mg/kg
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Administration:Intravenous injection (i.v.); 30 min before RM-1 inoculation and then once daily for 6 consecutive days
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Result:Prevented RM-1-induced p-ERK1/2 upregulation in the ipsilateral L3/L4 dorsal horn, indicating suppression of neuronal hyperactivity.
Prevented RM-1-induced GFAP upregulation in the ipsilateral L3/L4 dorsal horn, indicating suppression of astrocyte hyperactivity.
Did not alter basal p-ERK1/2, total ERK1/2 or GFAP expression in HBSS-inoculated mice.
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Animal Model:8-week-old male CD1 mice paclitaxel-induced peripheral neuropathic pain mouse model[1]
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Dosage:10 mg/kg
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Administration:Intravenous injection (i.v.); once daily; for 7 consecutive days starting on day 9 after the first paclitaxel injection
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Result:Reduced paclitaxel-induced bilateral mechanical allodynia, heat hyperalgesia and cold hyperalgesia on days 11, 13 and 15 after the first paclitaxel injection.
Did not alter basal responses to mechanical, heat or cold stimuli in vehicle-treated mice.
Maintained normal locomotor function.
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Animal Model:8-week-old male CD1 mice paclitaxel-induced dorsal horn neuronal and astrocyte hyperactivity model[1]
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Dosage:10 mg/kg
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Administration:Intravenous injection (i.v.); once daily; for 7 consecutive days starting on day 9 after the first paclitaxel injection
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Result:Prevented paclitaxel-induced p-ERK1/2 and GFAP upregulation in the lumbar enlargement dorsal horn on day 15 after the first paclitaxel injection.
Attenuated paclitaxel-induced increases in membrane nNOS level and PSD-95-nNOS binding density in the lumbar dorsal horn.
Did not significantly change basal PSD-95 level or total nNOS and PSD-95 levels.
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Animal Model:8-week-old male SD rat SNL-induced neuropathic pain rat model[2]
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Dosage:60 mg/kg/day
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Administration:Intragastric administration (i.g.); once daily; for 11 days
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Result:Reduced SNL-induced mechanical hyperalgesia and thermal pain.
Maintained antinociceptive activity during repeated dosing.
Did not produce analgesic tolerance during the 11-day administration period.
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Animal Model:8-week-old male SD rat SNL-induced neuropathic pain mouse model[2]
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Dosage:60 mg/kg/day
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Administration:Intragastric administration (i.g.); once daily; for 28 days
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Result:Maintained long-term antinociceptive activity during 28 days of repeated dosing.
Produced sustained relief of SNL-induced neuropathic pain without analgesic tolerance.
Showed a better long-term tolerance profile than pregabalin, which produced severe analgesic tolerance under the same 28-day treatment duration.
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Animal Model:Adult SD rat tMCAO model[3]
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Dosage:0.5, 1, 2, 4 mg/kg
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Administration:Intravenous injection (i.v.); single administration at 60 min after reperfusion
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Result:Reduced infarct volume and neurological score dose-dependently at 48 h after tMCAO in male and female rats.
Showed an effective dose of 1 mg/kg.
At 2 mg/kg, showed effects comparable with edaravone dexborneol (ED).
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Animal Model:Adult SD rat tMCAO long-term functional recovery model[3]
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Dosage:2 mg/kg/day
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Administration:Intravenous injection (i.v.); once daily; for 3 or 7 consecutive days after cerebral ischemia
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Result:Reduced modified Neurological Severity Score (mNSS) and foot faults on day 28 after tMCAO.
Improved spatial learning in Morris water maze during days 30-35 after stroke.
Improved long-term neurological deficit, motor function and spatial learning without changing swimming speed.
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Animal Model:8-week-old C57BL/6 mice photothrombotic stroke model[3]
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Dosage:2 mg/kg
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Administration:Intravenous injection (i.v.); two doses at 2 and 26 h after ischemia
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Result:Reduced contralateral forelimb foot faults in the grid-walking test.
Reduced asymmetry index in the cylinder test.
Reduced infarct volume on day 7 after ischemia.
Improved motor function and reduced permanent ischemic injury.
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Animal Model:Adult SD rat photothrombotic permanent stroke delayed treatment model[3]
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Dosage:2 mg/kg
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Administration:Intravenous injection (i.v.); first dose at 6 or 12 h after ischemia and second dose 24 h after the first dose
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Result:Improved motor function in the grid-walking test on day 7 after ischemia.
Improved somatosensory function in the modified sticky-tape test on day 7 after ischemia.
Reduced infarct volume measured by Nissl staining.
Showed a therapeutic time window of up to 12 h after permanent ischemia.
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Animal Model:8-week-old C57BL/6 mice UCMS-induced anxiety and depression model[3]
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Dosage:1, 2 mg/kg
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Administration:Intravenous injection (i.v.); single administration during 2-12 h after the end of 28-day UCMS exposure
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Result:At 2 mg/kg, reversed UCMS-induced behavioral modifications at 60 min after injection.
Increased time spent in open arms in the EPM test.
Decreased latency to feed in the NSF test.
Reduced immobility time in the FST and TST.
Increased sucrose water preference in the SPT.
Did not affect locomotor activity or food consumption.
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Animal Model:8-week-old C57BL/6 mice tMCAO-induced anxiety and depression model[3]
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Dosage:2 mg/kg/day
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Administration:Intravenous injection (i.v.); once daily; for 7 consecutive days after stroke
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Result:Prevented tMCAO-induced behavioral modifications.
Increased sucrose water preference in the SPT on day 7 after stroke.
Decreased latency to feed in the NSF test on day 10 after stroke.
Did not affect food consumption.
Chemical Information
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CAS No. 2486316-20-3
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Masse moléculaire 464.38
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Formule C24H27Cl2NO4
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SMILES
C[C@]12[C@H](C[C@](CC2)([H])C1(C)C)OC(C3=C(C=C(C=C3)NCC4=C(C(Cl)=CC(Cl)=C4)O)O)=O
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Livraison
Room temperature in continental US; may vary elsewhere.
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Stockage
Please store the product under the recommended conditions in the Certificate of Analysis.
Pureté et documentation
Références
[1]. 1. Wei W et al. A Compound Mitigates Cancer Pain and Chemotherapy-Induced Neuropathic Pain by Dually Targeting nNOS-PSD-95 Interaction and GABAA Receptor. Neurotherapeutics. 2021 Oct;18(4):2436-2448. [Content Brief]
[2]. 2. Li J et al. A pain killer without analgesic tolerance designed by co-targeting PSD-95-nNOS interaction and α2-containning GABAARs. Theranostics. 2021 Apr 3;11(12):5970-5985.2. Li J et al. A pain killer without analgesic tolerance designed by co-targeting PSD-95-nNOS interaction and α2-containning GABAARs. Theranostics. 2021 Apr 3;11(12):5970-5985.2. Li J et al. A pain killer without analgesic tolerance designed by co-targeting PSD-95-nNOS interaction and α2-containning GABAARs. Theranostics. 2021 Apr 3;11(12):5970-5985. [Content Brief]
[3]. 3. Wu H et al. Preclinical evaluation of ZL006-05, a new antistroke drug with fast-onset antidepressant and anxiolytic effects. Stroke Vasc Neurol. 2023 Dec 29;8(6):463-474. [Content Brief]
Calculators
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
ZL006-05 Related Classifications
HY-184108 Related Classifications
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- ZL006-05
- 2486316-20-3
- iGluR
- GABA Receptor
- NO Synthase
- central sensitization
- spinal dorsal horn
- anterior cingulate cortex
- lamina II neuron
- lamina I excitatory neuron
- HEK293
- SNL model
- neuropathic pain
- analgesic tolerance
- pregabalin
- p-ERK1/2
- GFAP
- mechanical allodynia
- heat hyperalgesia
- cold hyperalgesia
- spontaneous pain
- tMCAO
- photothrombotic stroke
- ischemic stroke
- infarct volume
- neurological score
- grid-walking test
- cylinder test
- UCMS
- elevated plus maze
- novelty-suppressed feeding
- forced swim test
- tail suspension test
- sucrose preference test
- blood-brain barrier
- pharmacokinetics
- toxicokinetics
- long-term toxicity
- Inhibitor
- inhibitor
- inhibit