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

Cannabimimetic Properties of Ajulemic Acid

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   “Side effects of marijuana-based drugs and synthetic analogs of Δ9-tetrahydrocannabinol (Δ9-THC), including sedation and dysphoria, have limited their therapeutic application. Ajulemic acid (AJA), a side-chain synthetic analog of Δ8-THC-11-oic acid, has been reported to have anti-inflammatory properties without producing undesired psychoactive effects. Moreover, it has been suggested that AJA does not interact with cannabinoid receptors to produce its pharmacological effects. The aim of the present study was to conduct a thorough evaluation of the pharmacological effects of AJA then to determine whether actions at cannabinoid receptor (CB)1 mediated these effects… These studies demonstrated that AJA shares a number of CB1-mediated pharmacological properties with Δ9-THC, including cannabimimetic, discriminative stimulus, and antihyperalgesic effects. Furthermore, a separation between doses that produced antinociception and those that produced the other pharmacological effects in mice was not observed. Moreover, AJA showed nearly equipotency for therapeutic efficacy in the CFA model and for substitution in Δ9-THC discrimination. In summary, this study shows that AJA, like Δ9-THC, exhibits psychoactive and therapeutic effects at nearly equal doses in preclinical models, suggesting similar limitations in their putative therapeutic profiles.”

“Cannabis sativa (marijuana plant) has been used since antiquity for its presumed therapeutic, as well as for its euphoric effects. Although Δ9-tetrahydrocannabinol (Δ9-THC) has been identified as the major psychoactive ingredient in C. sativa, difficulty in dissociating unwanted side effects, such as sedation and psychotropic effects, from therapeutic effects has limited clinical application of Δ9-THC-based drugs. For example, dronabinol, an orally administered synthetic version of Δ9-THC, has been developed as an appetite stimulant and antiemetic for use in chronic diseases such as AIDS and cancer. In addition, recent evidence suggests oral Δ9-THC may be effective as an adjunct to opioid analgesics. The therapeutic utility of Δ9-THC, however, has been limited due to patient complaints of dysphoria and unpleasant subjective effects. Previous research has suggested that Δ9-THC carboxylic acid, one of the acid metabolites of Δ9-THC, lacks psychoactive properties of the parent compound and yet retains antinociceptive and other effects. Since this metabolite has a relatively low potency, structural changes that increased potency and stability of Δ9-THC analogs in previous structure-activity relationship studies were applied to the structure Δ9-THC carboxylic acid. The resulting compound, ajulemic acid (AJA), substitutes a 1′,1-dimethylheptyl side chain for the pentyl group of Δ9-THC and changes the Δ9-THC core structure to a more stable confirmation, Δ8-THC (Fig. 1).”

Fig. 1

 
“To date, the efficacy of AJA has been demonstrated in numerous pain and inflammation studies…”
 
“These findings also underscore the importance of thoroughly evaluating the pharmacological characteristics of novel Δ9-THC-like compounds…”
 

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

Effect of the cannabinoid ajulemic acid on rat models of neuropathic and inflammatory pain.

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Abstract

   “There is increasing evidence that cannabinoid agonists alleviate the abnormal pain sensations associated with animal models of neuropathic and inflammatory pain. However, cannabinoids produce a number of motor and psychotropic side effects. In the present study we found that systemic administration of the cannabinoid acid derivative 1′,1′-dimethylheptyl-delta-8-tetrahydrocannabinol-11-oic acid (ajulemic acid, IP-751) and the non-selective cannabinoid receptor agonist HU-210 reduced mechanical allodynia in a nerve-injury induced model of neuropathic pain and in the CFA-induced model of inflammatory pain. In contrast, HU-210, but not ajulemic acid reduced motor performance in the rotarod test. These findings suggest that ajulemic acid reduces abnormal pain sensations associated with chronic pain without producing the motor side effects associated with THC and other non-selective cannabinoid receptor agonists.”

http://www.ncbi.nlm.nih.gov/pubmed/15925096

Ajulemic acid (IP-751): Synthesis, proof of principle, toxicity studies, and clinical trials

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Abstract

  “Ajulemic acid (CT-3, IP-751, 1′,1′-dimethylheptyl-Delta8-tetrahydrocannabinol-11-oic acid) (AJA) has a cannabinoid-derived structure; however, there is no evidence that it produces psychotropic actions when given at therapeutic doses. In a variety of animal assays, AJA shows efficacy in models for pain and inflammation. Furthermore, in the rat adjuvant arthritis model, it displayed a remarkable action in preventing the destruction of inflamed joints. A phase-2 human trial with chronic, neuropathic pain patients suggested that AJA could become a useful drug for treating this condition. Its low toxicity, particularly its lack of ulcerogenicity, further suggests that it will have a highly favorable therapeutic index and may replace some of the current anti-inflammatory/analgesic medications. Studies to date indicate a unique mechanism of action for AJA that may explain its lack of adverse side effects.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2751505/