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Shionogi has also disclosed two series of thiazine-containing CB2 agonists, of which compounds 8 and 9 are examples [113, 114]. Selectivity data for several of the compounds with regard to CB2/CB1 affinities are described. For example, compound 8 binds to CB2 with a Ki value of 0.3 nM and a Ki value of >5000 nM for CB1. Compound 9 displayed a Ki value of 1.2 nM at the CB2 receptor and 80 nM at the CB1 receptor. When dosed orally at 100 mg/kg in a mouse pruritis model, this compound reduced scratching by 98% relative to control animals.

Structure 22

Structure 22

Shionogi has disclosed a series of amide-containing CB2 modulators stated to be useful in the treatment of inflammation, nephritis, pain, allergies, rheumatoid arthritis, multiple sclerosis, brain tumors and glaucoma [115]. Compound 10 was found to bind to the CB2 receptor with a Ki value of 4 nM, with very little affinity for CB1 (Ki < 5 |M).

Structure 23

Structure 23

Recently 1,8-naphthyridin-4(1H)-on-3-carboxamide derivatives (11) were synthesized as new ligands of cannabinoid receptors [116]. Some of these compounds possess a greater affinity for the CB2 receptor than for the CB1 receptor. Compound 7-chloro-N-cyclohexyl-1-(2-morpholin-4-ylethyl)-1,8-naph-thyridin-4(1H)-on-3-carboxamide (12) revealed a good CB2 selectivity (CB1, Ki = 1 |M; CB2, Ki = 25 ± 1.8 nM).

Indole derivatives were prepared and tested for their CB1 and CB2 receptor affinities [117]. Three new highly selective CB2 receptor agonists were identified, namely JWH-120 (CB1, Ki = 1054 ± 31 nM; CB2, Ki = 6.1 ± 0.7 nM), JWH-151 (CB1, Ki >10000 nM; CB2, Ki = 30 ± 1.1 nM) and JWH-267 (CB1, Ki = 381 ± 16 nM; CB2, Ki = 7.2 ± 0.14 nM).

Structure 24

Structure 24

Structure 25


C. sativa L. has been used throughout history not only for its fiber, but also as a medicinal plant. It has been the object of scientific research over the past 150 years. After the isolation of the plant's constituents, biochemical work led to the identification of two receptors and of endogenous cannabinoids. Over the last decade numerous synthetic agonists and antagonists have been prepared. We may be approaching an important goal in cannabinoid research - the use of cannabinoids in medicine - which has been the dream of several generations of scientists.


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Cannabinoids as Therapeutics Edited by R. Mechoulam © 2005 Birkhäuser Verlag/Switzerland

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Arthritis Joint Pain

Arthritis Joint Pain

Arthritis is a general term which is commonly associated with a number of painful conditions affecting the joints and bones. The term arthritis literally translates to joint inflammation.

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