Cannabinoids Chemistry and Medicine

Except for some work on the topical antibiotic properties of cannabinoid acids [49], medicinal chemical work in this field essentially stopped until 1964, when the major active constituent, A -THC, was isolated in a pure form and its structure was elucidated [50]. Since then, thousands of papers on the chemistry, pharmacology, metabolism and clinical effects of A -THC (1) have been published. On the basis of the knowledge accumulated, a considerable... 

The cannabinoid field was reviewed in Progress in Medicinal Chemistry Volume 35. Since that time great advances have been made in our understanding of cannabinoid receptor pharmacology. Many novel ligands have been discovered and several are expected to have exciting clinical utility. Medicinal chemistry approaches to the modulation of cannabinoid receptors are extensively reviewed in Chapter 6. 

Razdan et al., Drugs Derived from Cannabinoids. 2 la Basic Esters of Nitrogen and Carbocyclic Analogs , Journal of Medicinal Chemistry, vol. 19, No. 4, 1976. 

Hanus, L., Gopher, A., Almog, S., and Mechoulam, R. (1993) Two new unsaturated fatty acid ethanola-mides in brain that bind to the cannabinoid receptor. Journal of Medicinal Chemistry 36 3032-3034. 

Fichera, M., Cruciani, G., Bianchi, A., and Musumarra, G. (2000) A 3D-QSAR study on the structural requirements for binding to CB(1) and CB(2) cannabinoid receptors. Journal of Medicinal Chemistry 43 2300-2309. 

Van der Stelt, M., Van Kuik, J.A., Bari, M., van Zadelhoff, G., Eeeflang, B.R., Veldink, G.A. et al. (2002) Oxygenated metabolites of anandamide and 2-arachidonoyl-glycerol conformational analysis and interaction with cannabinoid receptors, membrane transporter and fatty acid amide hydrolase. Journal of Medicinal Chemistry 45 3709-3720. 

M. W., Nguyen, H.Q., Patel, V.F., Tomlinson, S.A., White, R.D., Xia, X., and Hitchcock, S.A. (2008) Discovery and optimization of a novel series of N-arylamide oxadiazoles as potent, highly selective and orally bioavailable cannabinoid receptor 2 (CB2) agonists. Journal of Medicinal Chemistry, 51, 5019-5034. 

Methoxy-N-alkyl isatin acylhydrazone derivatives as a novel series of potent selective cannabinoid receptor 2 inverse agonists design, synthesis, and binding mode prediction. Journal of Medicinal Chemistry, 52, 433-444. 

Wang, H., Dully R.A., Boykow, G.C., Chackalamannil, S., and Madison, V.S. (2008) Identification of novel cannabinoid CBl receptor antagonists by using virtual screening with a pharmacophore model. Journal of Medicinal Chemistry, 51, 2439-2446. 

Salo, O.M., Raitio, K.H., Savinainen, J.R., Nevalainen, T, Lahtela-Kakkonen, M., Laitinen, J.T, Jarvinen, T, and Poso, A. (2005) Virtual screening of novel CB2 ligands using a comparative model of the human cannabinoid CB2 receptor. Journal of Medicinal Chemistry, 48 (23), 7166-7171. 

From a previous medicinal chemistry campaign, novel substituted benzene sulfonamides were identified as selective cannabinoid CB2 receptor ligands. In order to improve upon the selectivity of these compounds, the central benzene template was modified to accommodate a more lipophilic bicyclic system. The synthesis, SAR and in vivo efficacy of this novel series of CB2 ligands will be presented. 

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