Synthesis and pharmacology of the isomeric methylheptyl-Δ8-tetrahydrocannabinols

Huffman, John W.; Liddle, John; Duncan, Sammy G.; Yu, Shu; Martin, Billy R.; Wiley, Jenny L.

doi:10.1016/s0968-0896(98)80014-x

Cited by 29 publications

(25 citation statements)

References 19 publications

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“…For the CB 1 -agonist, ACEA, this concentration was 50 nM, corresponding to more than 30 times its Ki for CB 1 -receptors (1.4 nM, according to Hillard et al, 1999). Although the concentration of the CB 2 -agonist, JWH015, was the same (50 nM), it corresponds to only 3 times its Ki value for CB 2 -receptors (Huffman et al, 1998;Huffman, 2000). Underdown et al (2005), using different selective agonists but with similar pharmacological properties, could not observe a cardioprotective effect with either CB 1 -or CB 2 -receptor activation in rat isolated hearts.…”

Section: Discussionmentioning

confidence: 94%

Endothelial CB1-receptors limit infarct size through NO formation in rat isolated hearts

et al. 2007

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Section: Discussionmentioning

confidence: 94%

Endothelial CB1-receptors limit infarct size through NO formation in rat isolated hearts

et al. 2007

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“…21 Thus, the Bayer–Villiger oxidation of 17 provided the acetate 18 which was hydrolyzed and the resulting alcohol 19 oxidized to the 17-ketone 20 . Its subsequent Wittig reaction with the ylide, generated from the phosphonium salt 21 , 22 yielded a mixture of olefinic compounds. As expected, 23 the isomer 22 with Z -geometry of the introduced double bond was a major product.…”

Section: Resultsmentioning

confidence: 99%

Removal of the 20-methyl group from 2-methylene-19-nor-(20S)-1α,25-dihydroxyvitamin D3 (2MD) selectively eliminates bone calcium mobilization activity

Barycki

Siciński

Plum

et al. 2009

Bioorganic & Medicinal Chemistry

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The 18-nor (7), 21-nor (8) and 18,21-dinor (9) analogs of (20S)-1α,25-dihydroxy-2-methylene-19-norvitamin D3 (6, 2MD) were prepared by convergent syntheses. The known phosphine oxide 10 was coupled by the Wittig–Horner process with the corresponding C,D-fragments (13–15), obtained by a multi-step procedure from commercial vitamin D2. The goal of our studies was to examine the influence of removal of the methyl groups located at carbons 13 and 20 on the biological potency of 2MD in the hope of finding analogs with improved therapeutic profiles. Replacement of the 20-methyl with hydrogen in 2-methylene-19-nor-(20S)-1α,25-dihydroxyvitamin D3 (2MD) did not affect binding to the rat vitamin D receptor and had little effect on transcription activity and on HL-60 differentiation. However, the mobilization of calcium from bone was largely eliminated while intestinal calcium transport remained strong. Curiously, removal of both the C-13-methyl and 20-methyl restored slightly the bone calcium mobilizing activity. Thus, the 21-nor analog of 2MD may provide a potent analog with a greater margin of safety than 2MD.

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“…Although CB 1 and CB 2 have been detected in the immune system [6], CB 2 is particularly abundant [36]. In the present study, we have evaluated the effect of CB 2 activation on the immune system by using JWH 133, a synthetic, CB 2 -selective cannabinoid agonist [14,37]. Using an experi-mental model of EAU, we demonstrated that JWH 133 induced a strong, suppressive effect in the immune system and suppressed EAU in a dose-dependent manner.…”

Section: Discussionmentioning

confidence: 99%

Anti-inflammatory property of the cannabinoid receptor-2-selective agonist JWH-133 in a rodent model of autoimmune uveoretinitis

Cheng

Chen

et al. 2007

Journal of Leukocyte Biology

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Previous studies have shown that cannabinoids have anti-inflammatory and immune-modulating effects, but the precise mechanisms of action remain to be elucidated. In this study, we investigated the effect of JWH 133, a selective agonist for cannabinoid receptor 2, the main receptor expressed on immune cells, in a model of autoimmune disease, experimental autoimmune uveoretinitis (EAU). JWH 133 suppressed EAU in a dose-dependent manner (0.015-15 mg/kg), and the suppressive effect could be achieved in the disease-induction stage and the effector stage. Leukocytes from mice, which had been treated with JWH 133, had diminished responses to retinal peptide and mitogen Con A stimulation in vitro. In vivo JWH 133 treatment also abrogated leukocyte cytokine/chemokine production. Further in vitro studies indicated that JWH 133 down-regulated the TLR4 via Myd88 signal transduction, which may be responsible for its moderate, suppressive effect on antigen presentation. In vivo JWH 133 treatment (1 mg/kg) also suppressed leukocyte trafficking (rolling and infiltration) in inflamed retina as a result of an effect on reducing adhesion molecules CD162 (P-selectin glycoprotein ligand 1) and CD11a (LFA-1) expression on T cells. In conclusion, the cannabinoid agonist JWH 133 has a high in vivo, anti-inflammatory property and may exert its effect via inhibiting the activation and function of autoreactive T cells and preventing leukocyte trafficking into the inflamed tissue.

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Synthesis and pharmacology of the isomeric methylheptyl-Δ8-tetrahydrocannabinols

Cited by 29 publications

References 19 publications

Endothelial CB1-receptors limit infarct size through NO formation in rat isolated hearts

Endothelial CB1-receptors limit infarct size through NO formation in rat isolated hearts

Removal of the 20-methyl group from 2-methylene-19-nor-(20S)-1α,25-dihydroxyvitamin D3 (2MD) selectively eliminates bone calcium mobilization activity

Anti-inflammatory property of the cannabinoid receptor-2-selective agonist JWH-133 in a rodent model of autoimmune uveoretinitis

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