HU-308
HU-308.png
Clinical data
Routes of
administration
Injection, oral, eyedrops
Legal status
Legal status
Pharmacokinetic data
MetabolismLiver
ExcretionKidneys
Identifiers
  • [(1R,2R,5R)-2-[2,6-Dimethoxy-4-(2-methyloctan-2-yl)phenyl]-7,7-dimethyl-4-bicyclo[3.1.1]hept-3-enyl]methanol
CAS Number
PubChem CID
ChemSpider
UNII
ChEBI
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC27H42O3
Molar mass414.630 g·mol−1
3D model (JSmol)
  • CCCCCCC(C)(C)C1=CC(=C(C(=C1)OC)[C@H]2C=C([C@@H]3C[C@H]2C3(C)C)CO)OC
  • InChI=1S/C27H42O3/c1-8-9-10-11-12-26(2,3)19-14-23(29-6)25(24(15-19)30-7)20-13-18(17-28)21-16-22(20)27(21,4)5/h13-15,20-22,28H,8-12,16-17H2,1-7H3/t20-,21-,22+/m0/s1
  • Key:CFMRIVODIXTERW-FDFHNCONSA-N
 ☒NcheckY (what is this?)  (verify)

HU-308 (also known as HU308, PPP-003 and ARDS-003) is a cannabidiol (CBD)-derivative drug that acts as a potent cannabinoid agonist. It is highly selective for the cannabinoid-2 receptor (CB2 receptor) subtype, with a selectivity more than 5,000 times greater for the CB2 receptor than the CB1 receptor.[1][2][3] The synthesis and characterization of HU-308 took place in the laboratory of Raphael Mechoulam at the Hebrew University of Jerusalem (the HU in HU-308) in the late 1990s. The pinene dimethoxy-DMH-CBD derivative HU-308 was identified as a potent peripheral CB2-selective agonist in studies in 1990[1] and 1999.[2]

HU-308 has shown interesting properties such as anti-inflammatory, analgesic, neuroprotective, antitumor and anti-osteoporitic (anti-bone-loss) effects, and has been used as a pharmacological tool in numerous cannabinoid studies in this field. The US National Institutes of Health (NIH) database notes it for being pivotal to the advance of findings in attenuating oxidative stress, inflammatory response, and apoptosis (programmed cell death).[4] HU-308 is also classified as a non-steroidal anti-inflammatory drug (NSAID).[5]

Pharmacology[edit]

Osteoporosis[edit]

Cannabinoid receptors were first implicated in the regulation of bone mass in 2004,[6] when cannabinoid-2 (CB2) knockout mice were found to have markedly accelerated age-related trabecular bone loss and cortical expansion accompanied by increased activity of trabecular osteoblasts, increased numbers of osteoclasts, and decreased numbers of diaphyseal osteoblast precursors.[7] CB2 receptors were expressed in osteoblasts, osteocytes, and osteoclasts. The selective CB2 agonist HU-308, but not the CB1 receptor agonist noladin ether, attenuated ovariectomy-induced bone loss and markedly stimulated cortical thickness through the suppression of osteoclast number and stimulation of endocortical bone formation.[7] Furthermore, HU-308 dose dependently increased the number and activity of endocortical osteoblasts and restrained trabecular osteoclastogenesis by inhibiting proliferation of osteoclast precursors.[7] These results, coupled with CB2 but not CB1 receptor mRNA expression during osteoblastic differentiation, suggested a role for CB2 receptors in bone remodeling. Such a role of CB2 but not CB1 receptors is also supported by a 2005 systematic genetic association study overseen by molecular biologist Meliha Karsak in postmenopausal osteoporosis patients, which found a statistically significant association of single polymorphisms (P=0.0014) and haplotypes (P=0.0001) that encompassed the CNR2 gene on human chromosome 1p36, while finding no convincing association for the psychotropic CNR1 gene.[8] It is the non-psychotropic cannabinoid receptor type 2 gene that is found to be so strongly associated with human osteoporosis as P value of 0.0001.[8]

Neuroinflammation[edit]

HU308 promotes neural progenitor (NP) proliferation and neurogenesis of neural stem cells,[9] promotes neuroprotection and neurorepair, activates phosphatidylinositol, and has important implications for neuronal survival under neuroinflammatory conditions occurring in animal models of neurodegenerative diseases, such as multiple sclerosis, Alzheimer disease, and Huntington's disease,[10][11][12][13] and upon acute ischemic brain injury.[14] Attenuation of the inflammatory response in the brain has also been reported by activation of CB2 receptors in a study of pial vessels forming the blood–brain barrier, using a model of lipopolysaccharide-induced encephalitis, wherein activation of CB2 receptors decreased adhesion molecules in the brain tissue and leukocyte-endothelial adhesion in the pial vessels.[15] HU-308 protects both liver and blood vessel tissues against hepatic ischemia and reperfusion (blood circulatory system) injury by attenuating oxidative stress, inflammatory response and apoptosis via inhibition of TNF-α.[16] The role of CB2 receptors in endothelial cell activation and endothelial/inflammatory cell interactions, being critical steps not only in reperfusion injury, but also atherosclerosis and other inflammatory disorders, is very important, because selective CB2 cannabinoid agonist HU-308 decreased TNF-α-induced ICAM-1 and VCAM-1 expression in human liver sinusoidal endothelial cells (HLSECs) expressing CB2 receptors, as well as the adhesion of human neutrophils to HLSECs in vitro.[17] HU-308 reduces blood pressure, blocks defecation, and elicits anti-inflammatory and peripheral analgesic activity.[2][18] Cannabidiol (CBD) and its potent derivatives (like HU-308) are generating considerable interest due to their beneficial neuroprotective, antiepileptic, anxiolytic, antipsychotic, anti-inflammatory and pain-relieving properties, and the CBD scaffold has become of increasing interest for medicinal chemists.[19]

Inflammation and immune modulation[edit]

HU-308 has an important functional outcome regarding the secretion of interleukin 6 (IL-6) and interleukin 10 (IL-10) with therapeutic immunomodulatory properties in vitro.[20] There is evidence that IL-6 may be used as an inflammatory marker for the more severe COVID-19 infections that have a poor prognosis for a favorable outcome because raised levels of IL-6 as well as troponin are associated with a poor prognosis in COVID-19.[21] Researchers have shown that HU-308 also mediates immune modulation in sepsis,[22] and displays antiallodynic activity (alleviates allodynic pain) in the rat hindpaw incision model of post-operative pain, is neuroprotective and improves motor performance in a mouse model of Huntington's disease.[23] A study has also shown that HU-308 dramatically fights the cytokine release syndrome (CRS, also called cytokine release storm) that is seen in many diseases and conditions, including acute respiratory distress syndrome (ARDS), COVID-19, sepsis, septic shock, systemic inflammatory response syndrome (SIRS), cytokine storm syndrome (CSS), multi-organ dysfunction syndrome (MODS), pneumonia, uveitis, corneal neuropathic pain hyperalgesia, photo-allodynia, burning, stinging, dryness and inflammation. The antinociceptive and anti-inflammatory effects of HU-308, but not Δ8THC or CBD, were mediated through CB2R, and reduces cytokine storms in the eye, where corneal damage can result in an inflammatory response involving the production of proinflammatory cytokines, neovascularization, recruitment of leukocytes, and release of neuropeptides producing inflammatory pain.[24][25][26] A CB2R agonist was first demonstrated to reduce corneal pain in a 2018 study on HU-308.[26] HU-308 is a selective and highly potent agonist at CB2R and has been shown to reduce lipopolysaccharide-induced intraocular inflammation.[26][27]

Multi-organ dysfunction and damage[edit]

While CB2 knockout mice developed enhanced inflammation and tissue injury from cisplatin-induced kidney damage, HU-308, working through the endocannabinoid system and the CB2 receptor, protected against cisplatin-induced kidney damage by attenuating inflammation and oxidative or nitrosative stress. Such selective CB2 agonists may represent a novel approach to prevent this complication of chemotherapy.[28] Activation of the CB2 receptors (expressed predominantly in immune cells and to a much lesser extent in other cell types [e.g., endothelial and parenchymal cells]) by recently recognized endogenous lipid mediators (the endocannabinoids) produced and present in virtually all tissues/organ systems,[29][30][31] or by selective synthetic CB2 agonists such as HU-308,[4] has been shown to protect against tissue damage in various experimental models of ischemic-reperfusion injury,[4][32] atherosclerosis/cardiovascular inflammation,[33][34][35] and neurodegenerative,[36] gastrointestinal[37][38] and other disorders by limiting inflammatory cell chemotaxis/infiltration, activation and interrelated oxidative/nitrosative stress.[39][40][41][42] In vivo, HU-308 treatment attenuated DSS-induced colitis mice associated with reduced colon inflammation and inhibited NLRP3 inflammasome activation in wild-type mice.[37] Furthermore, CB2 receptors are over-expressed in a variety of cancers, and CB2 activation may decrease the proliferation and growth of various cancer cells and tumors.[28][43] HU-308 was shown to reduce swelling, synovial joint inflammation and destruction, and lower circulating antibodies against Collagen I.[44]

ARDS-003[edit]

HU-308 is also known as ARDS-03 for its ARDS-fighting abilities. A collaboration study at the US National Institutes of Health (NIH) at George Mason University's (GMU's) National Center for Biodefense and Infectious Diseases Biomedical Research Laboratory (BRL) is examining ways to prevent lethal ARDS seen in COVID-19 patients.[45][46][47][48][49][50] Regulatory filings show that in late 2020, Tetra Bio-Pharma and Targeted Pharmaceutical designed short-to-mid-term studies to gather additional data on the benefits of ARDS-003 in SARS-CoV-2 infected animal models for the prevention of ARDS in COVID-19.[51] A former NIH deputy director is heading the GMU research on ARDS-003, which is a novel, sterile, injectable, optimized, nanoemulsion form of HU-308 that has successfully undergone safety and toxicology studies in accordance with USFDA oversight, which were required before submitting an investigational new drug (IND) application in the US and a clinical trial application (CTA) in Canada for a Phase 1 research study through the SARS-CoV-2 regulatory fast-track pathway.[49][52] The toxicology program was designed to the standards of the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) for enabling a first-in-human clinical trial; and included general toxicology data for two species-specific studies to assess toxicity in major organ systems (cardiovascular, respiratory, and nervous system) and genotoxicity, as well as the metabolism and pharmacokinetic distribution of the drug.[52] Tetra Bio-Pharma is the first endocannabinoid system (ECS) biotechnology company researching a cannabinoid treatment for ARDS and sepsis linked to COVID-19, pneumonia and other critical conditions, The ARDS-003 pharmaceutical drug gained FDA approval to begin Phase I and Phase II clinical trials in human subjects for the reduction of cytokine storm, sepsis, and ARDS in COVID-19.[45][52] GMU researchers are conducting three studies to assess the therapeutic efficacy of candidate interventions for COVID-19 in mouse models of angiotensin-converting enzyme 2 (ACE2) animals infected intranasally with SARS-CoV-2 to determine the survival advantage conferred by a therapeutic if an alternate course or dosing strategy needs to be followed, and to determine viral levels on day-three post-infection when viral load in the lungs is expected to peak.[53] Dalton Pharma is producing the injectable drug for the GMU effort.[54]

Legal status[edit]

Tetra Bio-Pharma[55][56][57][58] owns the intellectual property rights to HU-308.[59][60][61]

HU-308 is non-psychoactive and not scheduled at the federal level in the United States.[62] It is a Schedule I controlled substance in the state of Florida making it illegal to buy, sell, or possess there.[63]

References[edit]

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  55. ^ Nov 2018, Tetra Bio-Pharma Enters into Non-Binding Proposal to Acquire Panag Pharma Inc.
  56. ^ Jan 2019, Tetra Bio-Pharma Enters into Definitive Agreement to Acquire Panag Pharma Inc.
  57. ^ Apr 2019, Tetra Bio-Pharma Shareholders Approve the Acquisition of Panag Pharma
  58. ^ May 2019, Tetra Bio-Pharma Closes the Acquisition of Panag Pharma
  59. ^ USPTO, Compositions and methods for treatment of ocular inflammation and/or pain (Lynch & Kelly Jan 2017). In certain embodiments, the non-psychotropic phytocannabinoid is beta-caryophyllene or cannabidiol [CBD] and the synthetic cannabinoid is HU-433, HU-308, or a modified CBD such as CBD-DMH.
  60. ^ Justia, Compositions and methods for treatment of ocular inflammation and/or pain (Lynch & Kelly May 2015)
  61. ^ Lynch, Mary; Kelly, Melanie. "Patent 9549906 Composition & Methods for Treatment of Ocular Inflammation &/or Pain Jan 2017". U.S. Patent & Trademark Office. USPTO, Panag Pharma. Retrieved 20 February 2021.
  62. ^ 21 CFR — Schedules of controlled substances §1308.11 Schedule I.
  63. ^ Florida Statutes - Chapter 893 - Drug abuse prevention and control

See also[edit]