Tag Archives: cannabinoid

Marijuana-Derived Compound Targets Pain, Inflammation

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   “Researchers are developing a marijuana-derived synthetic compound to relieve pain and inflammation without the mood-altering side effects associated with other marijuana based drugs.

  They say the compound could improve treatment of a variety of conditions, including chronic pain, arthritis and multiple sclerosis. Their findings were presented at the 224th national meeting of the American Chemical Society, the world’s largest scientific society.

   The compound, called ajulemic acid, has produced encouraging results in animal studies of pain and inflammation. It is undergoing tests in a group of people with chronic pain and could be available by prescription within two to three years, the researchers say.

 “We believe that [the compound] will replace aspirin and similar drugs in most applications primarily because of a lack of toxic side effects,” says Sumner Burstein, Ph.D., lead investigator in the study and a professor in the department of biochemistry and molecular pharmacology at the University of Massachusetts Medical School in Worcester. “The indications so far are that it’s safe and effective,” he added.”

Read more: http://www.sciencedaily.com/releases/2002/08/020822071026.htm

The cannabinoid acids: nonpsychoactive derivatives with therapeutic potential.

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Abstract

   “The discovery of carboxylic acid metabolites of the cannabinoids (CBs) dates back more than three decades. Their lack of psychotropic activity was noted early on, and this resulted in a total absence of further research on their possible role in the actions of the CBs. More recent studies have revealed that the acids possess both analgesic and anti-inflammatory properties and may contribute to the actions of the parent drug. A synthetic analog showed similar actions at considerably lower doses. In this review, a brief survey of the extensive literature on metabolism of delta 9-tetrahydrocannabinol to the acids is presented, while more emphasis is given to the recent findings on the biological actions of this class of CBs. A possible mechanism involving effects on eicosanoids for some of these actions is also suggested. Finally, an analogy with a putative metabolite of anandamide, an endogenous CB, is discussed.”

http://www.ncbi.nlm.nih.gov/pubmed/10341359

Ajulemic acid, a synthetic cannabinoid acid, induces an antiinflammatory profile of eicosanoids in human synovial cells.

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“AIMS:

To better understand mechanisms whereby Ajulemic acid (AjA), a synthetic antiinflammatory cannabinoid, promotes resolution of acute and chronic inflammation in animal models, we investigated its influence on cyclooxygenase 2 (COX2) expression and eicosanoid production in human fibroblast-like synovial cells (FLS).”

“KEY FINDINGS:

AjA increased the steady state levels of COX2 mRNA in and arachidonic acid release from FLS. Treatment of FLS with AjA increased 15-deoxy-delta(12,14)-PGJ(2) (15d-PGJ(2)) production in a concentration dependent manner, but did not affect PGE(2) production significantly.”

“SIGNIFICANCE:

The capacity of AjA to increase selectively and markedly 15d-PGJ(2), an eicosanoid which facilitates resolution of inflammation, suggests that AjA may have value as a therapeutic agent for the treatment of rheumatoid arthritis (RA) and other diseases characterized by acute and chronic inflammation.”

http://www.ncbi.nlm.nih.gov/pubmed/18840450

Suppression of fibroblast metalloproteinases by ajulemic acid, a nonpsychoactive cannabinoid acid.

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Abstract

   “Production of matrix metalloproteinases (MMP) in joint tissue of patients with inflammatory arthritis facilitates cartilage degradation and bone erosion, and leads to joint deformities and crippling. Thus, MMPs are important targets for agents designed to treat inflammatory arthritis. Oral administration of ajulemic acid (AjA), a synthetic, nonpsychoactive cannabinoid acid, prevents joint tissue injury in rats with adjuvant arthritis. AjA binds to and activates PPARgamma directly. Therefore, we investigated the influence of AjA on MMP production in human fibroblast-like synovial cells (FLS), and examined the role of PPARgamma in the mechanism of action of AjA. FLS, treated or not with a PPARgamma antagonist, were treated with AjA then stimulated with TNFalpha or IL-1alpha. Release of MMPs-1, 3, and 9 was measured by ELISA. The influence of AjA on MMP-3 release from stimulated PPARgamma positive (PPAR+/-) and PPARgamma null (PPAR-/-) mouse embryonic fibroblasts (MEF) was also examined. Addition of AjA to FLS suppressed production of MMPs whether or not PPARgamma activation was blocked. Secretion of MMP-3 was also suppressed by AjA in both TNFalpha- and IL-1alpha-stimulated PPARgamma+/- and PPARgamma-/- MEF. Suppression of MMP secretion from FLS by AjA appears to be PPARgamma independent. Prevention by AjA of joint tissue injury and crippling in the rat adjuvant arthritis model may be explained in large part by inhibition of MMPs. These results suggest that AjA may be useful for treatment of patients with rheumatoid arthritis and osteoarthritis.”

http://www.ncbi.nlm.nih.gov/pubmed/16927387

Synthetic cannabinoid ajulemic acid exerts potent antifibrotic effects in experimental models of systemic sclerosis.

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BMJ Journals

“Cannabinoids modulate fibrogenesis in scleroderma.

Ajulemic acid (AjA) is a non-psychoactive synthetic analogue of tetrahydrocannabinol that can bind the peroxisome proliferator-activated receptor-γ (PPAR-γ). Recent evidence suggests a key role for PPAR-γ in fibrogenesis. To determine whether AjA can modulate fibrogenesis in murine models of scleroderma.”

“RESULTS:

AjA significantly prevented experimental bleomycin-induced dermal fibrosis and modestly reduced its progression when started 3 weeks into the disease. AjA strongly reduced collagen neosynthesis by scleroderma fibroblasts in vitro, an action which was reversed completely by co-treatment with a selective PPAR-γ antagonist.”

“CONCLUSIONS:

AjA prevents progression of fibrosis in vivo and inhibits fibrogenesis in vitro by stimulating PPAR-γ signalling. Since therapeutic doses of AjA are well tolerated in humans, it is suggested that AjA as an interesting molecule targeting fibrosis in patients with scleroderma.”

http://www.ncbi.nlm.nih.gov/pubmed/22492781

http://ard.bmj.com/content/71/9/1545

Antitumor effects of ajulemic acid (CT3), a synthetic non-psychoactive cannabinoid.

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Abstract

   “One of the endogenous transformation products of tetrahydrocannabinol (THC) is THC-11-oic acid, and ajulemic acid (AJA; dimethylheptyl-THC-11-oic acid) is a side-chain synthetic analog of THC-11-oic acid. In preclinical studies, AJA has been found to be a potent anti-inflammatory agent without psychoactive properties. Based on recent reports suggesting antitumor effects of cannabinoids (CBs), we assessed the potential of AJA as an antitumor agent. AJA proved to be approximately one-half as potent as THC in inhibiting tumor growth in vitro against a variety of neoplastic cell lines. However, its in vitro effects lasted longer. The antitumor effect was stereospecific, suggesting receptor mediation. Unlike THC, however, whose effect was blocked by both CB(1) and CB(2) receptor antagonists, the effect of AJA was inhibited by only the CB(2) antagonist. Additionally, incubation of C6 glioma cells with AJA resulted in the formation of lipid droplets, the number of which increased over time; this effect was noted to a much greater extent after AJA than after THC and was not seen in WI-38 cells, a human normal fibroblast cell line. Analysis of incorporation of radiolabeled fatty acids revealed a marked accumulation of triglycerides in AJA-treated cells at concentrations that produced tumor growth inhibition. Finally, AJA, administered p.o. to nude mice at a dosage several orders of magnitude below that which produces toxicity, inhibited the growth of subcutaneously implanted U87 human glioma cells modestly but significantly. We conclude that AJA acts to produce significant antitumor activity and effects its actions primarily via CB(2) receptors. Its very favorable toxicity profile, including lack of psychoactivity, makes it suitable for chronic usage. Further studies are warranted to determine its optimal role as an antitumor agent.”

http://www.ncbi.nlm.nih.gov/pubmed/11551521

Activation and Binding of Peroxisome Proliferator-Activated Receptor γ by Synthetic Cannabinoid Ajulemic Acid

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   “Ajulemic acid (AJA) is a synthetic analog of the tetrahydrocannabinol (THC) metabolite THC-11-oic acid; THC is a major active ingredient of the drug marijuana derived from the plant cannabis. AJA has potent analgesic and anti-inflammatory activity without the psychotropic action of THC. Unlike the nonsteroidal anti-inflammatory drugs, AJA is not ulcerogenic at therapeutic doses, making it a promising anti-inflammatory drug. However, the mechanism of AJA action remains unknown. Here we report that AJA binds directly and specifically to the peroxisome proliferator-activated receptor γ (PPARγ), a pharmacologically important member of the nuclear receptor superfamily. Functional assay indicates that AJA activates the transcriptional activity of both human and mouse PPARγ at pharmacological concentrations. Activation of PPARγ by AJA requires the AF-2 helix of the receptor, suggesting that AJA activates PPARγ through the ligand-dependent AF-2 function. AJA binding consistently enables PPARγ to recruit nuclear receptor coactivators. In addition, we show that AJA inhibits interleukin-8 promoter activity in a PPARγ-dependent manner, suggesting a link between the anti-inflammatory action of AJA and the activation of PPARγ. Finally, we find that AJA treatment induces differentiation of 3T3 L1 fibroblasts into adipocytes, a process mediated by PPARγ. Together, these data indicate that PPARγ may be a molecular target for AJA, providing a potential mechanism for the anti-inflammatory action of AJA, and possibly other cannabinoids. These studies also implicate other potential therapeutic actions of AJA through PPARγ activation in multiple signaling pathways.”

“The mood-altering drug marijuana derived from the hemp plant Cannabis sativa contains a group of biosynthetically related substances known collectively as cannabinoids. Tetrahydrocannabinol (THC), one of the major cannabinoids in marijuana, has potent analgesic and anti-inflammatory activities, but it also exhibits psychotropic effects, which limit its clinical application. Considerable effort has been expended toward the goal of creating nonpsychotropic cannabinoid derivatives that retain therapeutic actions but are free of psychotropic activity. A useful template for this search is the THC metabolite THC-11-oic acid…”

http://molpharm.aspetjournals.org/content/63/5/983.long

Ajulemic Acid, a Synthetic Nonpsychoactive Cannabinoid Acid, Bound to the Ligand Binding Domain of the Human Peroxisome Proliferator-activated Receptor γ*

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  “Ajulemic acid (AJA) is a synthetic analog of THC-11-oic acid, a metabolite of tetrahydrocannabinol (THC), the major active ingredient of the recreational drug marijuana derived from the plant Cannabis sativa. AJA has potent analgesic and anti-inflammatory activity in vivo, but without the psychotropic action of THC. However, its precise mechanism of action remains unknown. Biochemical studies indicate that AJA binds directly and selectively to the isotype γ of the peroxisome proliferator-activated receptor (PPARγ) suggesting that this may be a pharmacologically relevant receptor for this compound and a potential target for drug development in the treatment of pain and inflammation. Here, we report the crystal structure of the ligand binding domain of the γ isotype of human PPAR in complex with ajulemic acid, determined at 2.8-Å resolution. Our results show a binding mode that is compatible with other known partial agonists of PPAR, explaining their moderate activation of the receptor, as well as the structural basis for isotype selectivity, as observed previously in vitro. The structure also provides clues to the understanding of partial agonism itself, suggesting a rational approach to the design of molecules capable of activating the receptor at levels that avoid undesirable side effects.”

“AJA (also known as CT-3, IP-751, or 1′,1′-dimethylheptyl-Δ8-tetrahydrocannabinol-11-oic acid) was originally designed based on observations of the metabolic transformations of THC using the metabolite THC-11-oic acid as a template. AJA suppresses neuropathic pain in humans and prevents joint tissue injury in rat models of inflammatory arthritis. In all cases, these effects are observed without producing the motor side effects associated with THC.”

“In summary, our results show that AJA, as well as other THC analogs, in presenting specific binding together with minimal toxicity and good bioavailability may provide useful novel templates for rational drug design aimed at PPARγ regulation.”

 http://www.jbc.org/content/282/25/18625.long

Ajulemic acid: A novel cannabinoid produces analgesia without a “high”.

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Abstract

   “A long-standing goal in cannabinoid research has been the discovery of potent synthetic analogs of the natural substances that might be developed as clinically useful drugs. This requires, among other things, that they be free of the psychotropic effects that characterize the recreational use of Cannabis. An important driving force for this goal is the long history of the use of Cannabis as a medicinal agent especially in the treatment of pain and inflammation. While few compounds appear to have these properties, ajulemic acid (AJA), also known as CT-3 and IP-751, is a potential candidate that could achieve this goal. Its chemical structure was derived from that of the major metabolite of Delta9-THC, the principal psychotropic constituent of Cannabis. In preclinical studies it displayed many of the properties of non-steroidal anti-inflammatory drugs (NSAIDs); however, it seems to be free of undesirable side effects. The initial short-term trials in healthy human subjects, as well as in patients with chronic neuropathic pain, demonstrated a complete absence of psychotropic actions. Moreover, it proved to be more effective than placebo in reducing this type of pain as measured by the visual analog scale. Unlike the narcotic analgesics, signs of dependency were not observed after withdrawal of the drug at the end of the one-week treatment period. Data on its mechanism of action are not yet complete; however, the activation of PPAR-gamma, and regulation of eicosanoid and cytokine production, appear to be important for its potential therapeutic effects.”

http://www.ncbi.nlm.nih.gov/pubmed/15240185

Antihyperalgesic properties of the cannabinoid CT-3 in chronic neuropathic and inflammatory pain states in the rat.

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Abstract

   “CT-3 (ajulemic acid) is a synthetic analogue of a metabolite of Delta9-tetrahydrocannabinol that has reported analgesic efficacy in neuropathic pain states in man. Here we show that CT-3 binds to human cannabinoid receptors in vitro, with high affinity at hCB1 (Ki 6 nM) and hCB2 (Ki 56 nM) receptors. In a functional GTP-gamma-S assay CT-3 was an agonist at both hCB1 and hCB2 receptors (EC50 11 and 13.4 nM, respectively). In behavioural models of chronic neuropathic and inflammatory pain in the rat, oral administration of CT-3 (0.1-1 mg/kg) produced up to 60% reversal of mechanical hyperalgesia. In both models the antihyperalgesic activity was prevented by the CB1-antagonist SR141716A but not the CB2-antagonist SR144528. In the tetrad of tests for CNS activity, CT-3 (1-10 mg/kg, po) produced dose-related catalepsy, deficits in locomotor performance, hypothermia, and acute analgesia. Comparison of 50% maximal effects in the tetrad and chronic pain assays produced an approximate therapeutic index of 5-10. Pharmacokinetic analysis showed that CT-3 exhibits significant but limited brain penetration, with a brain/plasma ratio of 0.4 measured following oral administration, compared to ratios of 1.0-1.9 measured following subcutaneous administration of WIN55,212-2 or Delta9-THC. These data show that CT-3 is a cannabinoid receptor agonist and is efficacious in animal models of chronic pain by activation of the CB1 receptor. Whilst it shows significant cannabinoid-like CNS activity, it exhibits a superior therapeutic index compared to other cannabinoid compounds, which may reflect a relatively reduced CNS penetration.”

http://www.ncbi.nlm.nih.gov/pubmed/15936883