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Andreabae/sandbox
Clinical data
ATC code
  • none
Identifiers
  • (6aS,10aS)-9-(Hydroxymethyl)- 6,6-dimethyl- 3-(2-methyloctan-2-yl)- 6a,7,10,10a-tetrahydrobenzo [c]chromen-1-ol
CAS Number
PubChem CID
ChemSpider
UNII
Chemical and physical data
FormulaC25H38O3
Molar mass386.567 g/mol g·mol−1
3D model (JSmol)
  • Oc2cc(cc1OC([C@H]3C/C=C(\C[C@@H]3c12)CO)(C)C)C(C)(C)CCCCCC
  • InChI=1S/C25H38O3/c1-6-7-8-9-12-24(2,3)18-14-21(27)23-19-13-17(16-26)10-11-20(19)25(4,5)28-22(23)15-18/h10,14-15,19-20,26-27H,6-9,11-13,16H2,1-5H3/t19-,20-/m0/s1 ☒N
  • Key:SSQJFGMEZBFMNV-PMACEKPBSA-N ☒N
 ☒NcheckY (what is this?)  (verify)

Dexanabinol (HU-211 or ETS2101[1]) is a synthetic cannabinoid derivative that is the "unnatural" enantiomer of the potent cannabinoid agonist HU-210.[2] Although the drug was originally developed by a group from the Brettler Medical Research Center of Hebrew University in Jerusalem, Israel, Pharmos currently shares a licensing agreement with Hebrew University, and claims partnership for the development and commercialization of dexanabinol family compounds [3] [4] [5] Unlike other cannabinoid derivatives, HU-211 does not act as a cannabinoid receptor agonist, but instead has NMDA antagonist effects.[6] It therefore does not produce cannabis-like effects, but is anticonvulsant and neuroprotective, and is widely used in scientific research as well as currently being studied for practical applications such as treatment of head injury or stroke or cancer.[7][8][9] It was shown to be safe in clinical trials[10] and is currently undergoing Phase I trials for the treatment of brain cancer.[11]

Pharmacokinetics

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The pharmacokinetic profile of dexanabinol was determined in a phase I clinical trial involving 27 volunteers [12]. Volunteers received three different dosages of dexanabinol as 15 minute IV infusions in Cremophor-ethanol at 28 mg, 100 mg, or 200 mg. Results from this study reported that it has a rapid t1/2 = 2-3 min and slow t1/2= 8.5-9.5 hours. Plasma concentrations of dexanabinol were dose-related, as were AUC0-values. Total plasma clearance averaged 1734 ml/min across the three dosage groups, while the volume of distribution (Vd) ranged from 16.6 - 17.4 L/kg [13] [14].

Binding Properties

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Dexanabinol (HU-211) exhibits distinct binding properties from its enantiomer HU-210 [15] [16]. While HU-210 is a potent cannabinoid that acts on cannabinoid receptors, HU-211 stereospecifically binds and inhibits NMDA receptors. [3H] TCP binding assays have demonstrated that HU-211 acts on binding sites that are distinct from the binding sites of TCP, glutamate, and glycine. HU-211 is a more active inhibitor of NMDA receptors in the presence of glycine and glutamate, and is likely acting as a noncompetitive inhibitor. It is also understood that HU-211 shares the same binding site as another well-known competitive NMDA receptor antagonist, MK-801. When compared with MK-801, the KI of dexanabinol was determined to be 11 ± 1.3 mM.

Mechanism of Action

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Potential therapeutic uses

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Dexanabinol has been found to attenuate symptoms associated with glutamate excitotoxicity. Dexanabinol provides potential therapeutic benefits in alleviating symptoms related to CNS injury like stroke and brain trauma. It is well understood that glutamate excitotoxicity is a physiological response to CNS injury, and involves excitotoxic neurodegeneration due to several cellular changes like increased calcium influx, metabolic acidosis, and free radical generation from mitochondrial excitotoxicity [17]. The downstream macroscopic changes from injury-induced glutamate excitotoxicity include edema, increased intracranial pressure, inflammation, disruption of the blood brain barrier, impaired locomotor, memory, and cognitive function. HU-211 has progressed to clinical trials in several countries as a therapeutic agent for a variety of neurological disorders including glaucoma, stroke, head injuries, trauma, and cancer.

Ability to attenuate neurotoxic cell death

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As an NMDA receptor antagonist, HU-211 attenuates glutamate excitotoxicity by inhibiting the influx of calcium through NMDA receptor channels [18]. Initial studies on HU-211 demonstrated that NMDA-induced seizures in mice could be blocked by pre-treatment with HU-211 administration. Later studies investigating the neuroprotective properties of HU-211 after closed head injury in rats showed that HU-211 provides therapeutic benefits after injury by enhancing recovery for locomotor performance and memory [19]. Single intraperitoneal injection of HU-211 provided cerebroprotective effects within a 2-3 hour therapeutic window after injury by reducing edema and preventing injury-induced disruptions to the blood brain barrier disruption. HU-211 has also been demonstrated to attenuate increases in calcium that often accompany damage and induce further neuronal death. Gerbil and mice models of global and focal ischemia from stroke also demonstrated that HU-211 reduces neurodegeneration to brain areas that are most vulnerable to ischemic insult, like the hippocampus.

Antioxidant properties

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In vitro studies of the effects of HU-211 on neuronal cell cultures also identified HU-211’s unique antioxidant properties [20]. One hallmark of glutamate excitoxicity involves the excess-calcium induced corruption of mitochondria, and subsequent generation of reactive oxidative species (aka free radicals) that induce cell death. One major pathway by which free radicals induce cell death is through the disruption of the cell membrane by lipid peroxidation. HU-211 confers neuroprotective function against reactive oxidative species by scavenging free radicals, like peroxyl and hydroxyl molecules. Interestingly, this antioxidant property is unique to HU-211 and is not observed in other noncompetitive NMDA receptor molecules, like MK-801.

Anti-inflammatory properties

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HU-211 has also been demonstrated to provide anti-inflammatory effects by acting as an inhibitor of inflammatory agents like, COX-2, NFkB, and the cytokine TNF-α [21]. Inhibition of the inflammatory response after brain injury is suggested to be the mechanism by which HU-211 also reduces edema, blood brain barrier disruption, and intracranial pressure.

Clinical Trials

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Despite initial successes in characterizing the neuroprotective properties of HU-211 in several different animal models of trauma, ischemia, and axonal injuries, clinical trials in humans have been less successful [22]. Phase I and phase II clinical trials initially reported promising therapeutic value in reducing intracranial pressure after brain injury. Both phases of clinical trials confirmed the safety of IV administration at 48 or 150 mg. Additionally, a dose limiting toxicity was not observed at the two concentrations tested in these trials. Although Phase II clinical trials did not test the efficacy of dexanabinol, preliminary results reported a trend toward better and faster neurologic outcome. Phase III clinical trials confirmed that dexanabinol treatments were safe in humans, but also reported that it was not an efficacious treatment for traumatic brain injury. A Phase I clinical trial is currently underway in evaluating the safety and pharmokinetic profile of dexanabinol for brain cancer [23]. HU-211's unique ability to induce specific cell death in cancer cells makes it an attractive therapeutic pursuit .

Adverse side effects

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A 14 day toxicological study of HU-211 in rodents at neuroprotective dosages of HU-211 exhibited no physiological or toxicological effects. Clinical trials also yielded similar results, and thus confirmed the safety of HU-211 in humans. Interestingly, HU-211 provides neuroprotective efficacy to the same degree as other noncompetitive NMDA receptor antagonists, without undesirable side-effects, like ataxia, tremors, hyperactivity, and coma, that typically accompany NMDA receptor antagonists.

Synthesis

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As mentioned above, HU-211 is the [4S,3S]-7-hydroxy-Δ-tetrahydrocannabinol enantiomer to the potent hashish type HU-210, also known as [3R,4R]-7-hydroxy-Δ-tetrahydrocannabinol enantiomer [24]. HU-211 can be isolated from its homolog to a high degree of purity at more than 99.8% enantiomeric excess. The specific synthesis of HU-211 begins with the esterification of [1S,5R]-Myrtenol with pivalyl chloride. Afterwards, reacting this ester in acetic acid-acetic anyhydride yields 4-oxy-myrtenyl pivalate. Reduction of 4-oxymyrtenyl pivalate in tri-tert-butoxyaluminohydride produces 4-hydroxy-myrtenyl-pivalate. Silica gel chromatograpy of this compound (elution in10% ether in petroleum ether) leads to the acquisition of the pivalate ester. Reduction of the pivalate ester with lithium aluminum hydride leads to the formation of the [4S, 3S]-enantiomer, or HU-211.


References

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  1. ^ e-therapeutics Clinical Development Pipeline
  2. ^ Pop E (September 2000). "Nonpsychotropic synthetic cannabinoids". Current Pharmaceutical Design. 6 (13): 1347–60. doi:10.2174/1381612003399446. PMID 10903397.
  3. ^ Feigenbaum JJ, et al. (1989) Nonpsychotropic cannabinoid acts as a functional N-methyl-D-aspartate receptor blocker. Proceedings of the National Academy of Sciences of the United States of America 86(23):9584-9587.
  4. ^ Anonymous (2003) Dexanabinol. Drugs R&D 4(3):185-187.
  5. ^ Pop E (2000) Dexanabinol Pharmos. Current opinion in investigational drugs (London, England : 2000) 1(4):494-503.
  6. ^ Feigenbaum JJ; et al. (December 1989). "Nonpsychotropic cannabinoid acts as a functional N-methyl-D-aspartate receptor blocker". Proceedings of the National Academy of Sciences of the United States of America. 86 (23): 9584–7. doi:10.1073/pnas.86.23.9584. PMC 298542. PMID 2556719. {{cite journal}}: Explicit use of et al. in: |author= (help)
  7. ^ Biegon A; Joseph AB (August 1995). "Development of HU-211 as a neuroprotectant for ischemic brain damage". Neurological Research. 17 (4): 275–80. PMID 7477742.
  8. ^ Darlington CL (October 2003). "Dexanabinol: a novel cannabinoid with neuroprotective properties". IDrugs : the Investigational Drugs Journal. 6 (10): 976–9. PMID 14534855.
  9. ^ Vink R; Nimmo AJ (January 2009). "Multifunctional drugs for head injury". Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics. 6 (1): 28–42. doi:10.1016/j.nurt.2008.10.036. PMID 19110197.
  10. ^ Maas AI; et al. (January 2006). "Efficacy and safety of dexanabinol in severe traumatic brain injury: results of a phase III randomised, placebo-controlled, clinical trial". Lancet Neurol. 5 (1): 38–45. doi:10.1016/S1474-4422(05)70253-2. PMID 16361021. {{cite journal}}: Explicit use of et al. in: |author= (help)
  11. ^ University of California, San Diego "Synthetic Cannabinoid May Be Used as Brain Cancer Treatment". (28 September 2012) Laboratory Equipment. Retrieved 28 September 2012.
  12. ^ Brewster ME, et al. (1997) Clinical pharmacokinetics of escalating i.v. doses of dexanabinol (HU-211), a neuroprotectant agent, in normal volunteers. International journal of clinical pharmacology and therapeutics 35(9):361-365.
  13. ^ Anonymous (2003) Dexanabinol. Drugs R&D 4(3):185-187.
  14. ^ Brewster ME, et al. (1997) Clinical pharmacokinetics of escalating i.v. doses of dexanabinol (HU-211), a neuroprotectant agent, in normal volunteers. International journal of clinical pharmacology and therapeutics 35(9):361-365.
  15. ^ Feigenbaum JJ, et al. (1989) Nonpsychotropic cannabinoid acts as a functional N-methyl-D-aspartate receptor blocker. Proceedings of the National Academy of Sciences of the United States of America 86(23):9584-9587.
  16. ^ Mechoulam R, Lander N, Breuer A, & Zahalka J (1990) Synthesis of the individual, pharmacologically distinct, enantiomers of a tetrahydrocannabinol derivative. Tetrahedron: Asymmetry 1(5):315-318.
  17. ^ Lau A & Tymianski M (2010) Glutamate receptors, neurotoxicity and neurodegeneration. Eur J Physiol 460:525-542.
  18. ^ Lau A & Tymianski M (2010) Glutamate receptors, neurotoxicity and neurodegeneration. Eur J Physiol 460:525-542.
  19. ^ Shohami E, Novikov M, & Mechoulam R (1993) A nonpsychotropic cannabinoid, HU-211, has cerebroprotective effects after closed head injury in the rat. Journal of neurotrauma 10(2):109-119.
  20. ^ Biegon A & Joseph AB (1995) Development of HU-211 as a neuroprotectant for ischemic brain damage. Neurological research 17(4):275-280.
  21. ^ Vink R & Nimmo AJ (2009) Multifunctional drugs for head injury. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics 6(1):28-42.
  22. ^ Knoller N, et al. (2002) Dexanabinol (HU-211) in the treatment of severe closed head injury: a randomized, placebo-controlled, phase II clinical trial. Critical care medicine 30(3):548-554.
  23. ^ Kesari S (2013) Dexanabinol in Patients With Brain Cancer. (University of California, San Diego).
  24. ^ Mechoulam R, Lander N, Breuer A, & Zahalka J (1990) Synthesis of the individual, pharmacologically distinct, enantiomers of a tetrahydrocannabinol derivative. Tetrahedron: Asymmetry 1(5):315-318.

Category:Cannabinoids Category:NMDA receptor antagonists Category:Phenols Category:Benzochromenes Category:Alcohols Category:HU cannabinoids

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