HU-308

HU-308, aka HU308 and ARDS-003, is a CBD-derivative drug that acts as a potent cannabinoid agonist and which is a highly selective agonist for the CB₂ receptor subtype in particular, with a selectivity of over 5,000 times greater for CB₂ versus its selectivity for CB₁.[1][2] The synthesis and characterization took place in the laboratory of Prof. 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 decades ago as a potent peripheral CB2-selective agonist in Mechoulam et al 1990,[1] and in Hanus et al 1999.[2] HU-308 has shown very 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 contributing to the progress in this field (e.g., Hanus et al 1999;[2] Ofek et al 2006;[3] Rajesh et al 2007a,[4] 2007b;[5] Morales 2017[6]). Cannabinoid receptors were first implicated in the regulation of bone mass by Karsak et al (2004),[7] who found that CB2 knockout mice had 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 (Ofek et al 2006).[3] CB2 receptors were expressed in osteoblasts, osteocytes, and osteoclasts. The selective CB2 agonist HU-308, but not the CB1 agonist noladine ether, attenuated ovariectomy-induced bone loss and markedly stimulated cortical thickness through the suppression of osteoclast number and stimulation of endocortical bone formation.[3] Furthermore, HU-308 dose dependently increased the number and activity of endocortical osteoblasts and restrained trabecular osteoclastogenesis by inhibiting proliferation of osteoclast precursors.[3] 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 recent genetic association study in human samples of postmenopausal osteoporosis patients and matched female control subjects (Karsak et al 2005).[8] It has analgesic effects,[9] has an important functional outcome ~ the secretion of interleukins 6 (IL-6) and 10 (IL-10) with therapeutic immunomodulatory properties in vitro.[10]

HU308 promotes neural progenitor (NP) proliferation and neurogenesis of neural stem cells,[11] promotes neuroprotection and neurorepair, activates Phosphatidyl Inositol, 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 disease,[12][13][14][15] and upon acute ischemic brain injury.[16] 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 LPS-induced encephalitis (Ramirez et al 2012), wherein activation of CB2 receptors decreased adhesion molecules in the brain tissue and leukocyte-endothelial adhesion in the pial vessels.[17] HU-308 protects both liver and blood vessel tissues against hepatic ischemia and reperfusion (blood circulatory) injury by attenuating oxidative stress, inflammatory response and apoptosis via inhibition of TNF-α.[18] 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, turned out to be 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.[19] HU-308 reduces blood pressure, blocks defecation, and elicits anti-inflammatory and peripheral analgesic activity.[2] Currently, CBD (especially potent CBD derivatives like HU-308) generate considerable interest due to their beneficial neuroprotective, antiepileptic, anxiolytic, antipsychotic, and anti-inflammatory properties. Therefore, the CBD scaffold becomes of increasing interest for medicinal chemists.[6]

Researchers Dr. Melanie Kelly and Dr. C. Lehmann at Panag Pharma, now merged with Tetra Bio-Pharma,[20][21][22][23] which owns the IP rights to HU-308,[24][25] showed with Drs. J Sardinha and J Zhou that HU 308 also mediates immune modulation in sepsis,[26] as well as 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.[27] Continued work by Dr. MEM Kelly et al showed HU-308 also dramatically fights the cytokine release syndrome (CRS), also called cytokine release storm, that is seen in many diseases and conditions, including ARDS (acute respiratory distress syndrome), COVID-19, Sepsis, Septic Shock, SIRS (Systemic Inflammatory Response Syndrome), CRS, CSS, MODS (Multi-Organ Dysfunction Syndrome), Pneumonia, Uveitis, Corneal Neuropathic Pain (including Hyperalgesia, Photo-allodynia, Burning, Stinging, Dryness) & Inflammation, among others. The antinociceptive and anti-inflammatory effects of HU-308, but not Δ⁸THC or CBD, were mediated through CB₂R, and it reduces cytokine storms in the eye, importantly, where corneal damage can result in an inflammatory response that involves the production of proinflammatory cytokines, neovascularization, recruitment of leukocytes, and release of neuropeptides producing inflammatory pain.[28][29][30] The Thapa et al study on HU-308 in reducing Corneal Pain in 2018 is the first time a CB₂R agonist has been demonstrated to reduce corneal pain.[30] HU-308 is a selective and highly potent agonist at CB₂R and has previously been shown to reduce lipopolysaccharide-induced intraocular inflammation.[30][31]

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/nitrosative stress, and such selective CB₂ agonists may represent a promising novel approach to prevent this devastating complication of chemotherapy.[32] Activation of the cannabinoid-2 (CB2) receptors (expressed predominantly in immune cells, and also to a much less 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,[33][34][35] or by selective synthetic CB₂ agonists such as HU-308 in the pivotal advance by Rajesh et al (2007),[5] has been shown to protect against tissue damage in various experimental models of ischemic-reperfusion injury,[5][36] atherosclerosis/cardiovascular inflammation,[37][38][39] neurodegenerative,[40] gastrointestinal[41][42] and other disorders by limiting inflammatory cell chemotaxis/infiltration, activation and interrelated oxidative/nitrosative stress [14, 27-29]. In vivo, HU308 treatment attenuated DSS-induced colitis mice associated with reduced colon inflammation and inhibited NLRP3 inflammasome activation in wild-type mice.[41] Furthermore, CB2 receptors are over-expressed in a variety of cancers, and CB2 activation may decrease the proliferation/growth of various cancer cells and tumors.[32][43] HU-308 was shown to reduce swelling, synovial inflammation and joint destruction, in addition to lowering circulating antibodies against collagen I.[44]

HU-308, aka ARDS-03 for its ARDS fighting abilities, is currently being funded in a major collaboration study by Tetra Bio-Pharma and Targeted Pharmaceutical, LLC, in partnership with George Mason University and the NIH there at the university's top-level National Center for Biodefense and Infectious Diseases Biomedical Research Laboratory (BRL) against the killer condition Acute Respiratory Distress Syndrome (ARDS) seen in COVID-19 patients.[45][46][47][48][49][50] Dr. Lance Liotta, former Deputy Director of the NIH is heading the GMU research on ARDS-003, which is a novel, sterile, injectable, optimised, nano-emulsion form of HU-308 that has successfully undergone stringent safety and toxicology studies in accordance with U.S. FDA oversight, which were required before submitting an investigational new drug (IND) application in the USA and a clinical trial application (CTA) in Canada for a Phase 1 trial through the fast track Sars-CoV-2 regulatory paths.[49][51] The toxicology program was designed to the standards of the International Council for Harmonization (ICH) for enabling such 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, nervous system) and genotoxicity, as well as the metabolism and kinetics of distribution.[51] Tetra Bio-Pharma is the first endocannabinoid system (ECS) biotechnology company tackling ARDS and sepsis linked to COVID-19, pneumonia, tumors and other critical conditions, and its ARDS-003 pharmaceutical drug now has FDA approval to begin Phase I clinical trials in human subjects for cytokine storm, sepsis, and in particular, ARDS in Covid-19, hence its name "ARDS-003".[45][51]

• HU-210
• HU-320