Cannabinoid receptor ligands structures

Bisogno T (2008) Endogenous cannabinoids structure and metabohsm. J Neuroendociinol 20 1-9 Bisogno T, Melck D, Bobrov MY, Gretskaya NM, Bezuglov VV, De Petrocellis L, Di Marzo V (2000) N-acyl-dopamines novel synthetic CBl cannabinoid-receptor ligands and inhibitors of anandamide inactivation with cannabimemetic activity in vitro and in vivo. Biochem J 351 817-824... 

Suhara Y, Nakane S, Arai S, Takayama H, Waku K, Ishima Y, Sugiura T (2001) Synthesis and biological activities of novel structural analogues of 2-arachidonoylglycerol, an endogenous cannabinoid receptor ligand. Bioorg Med Chem Lett 11 1985-1988... 

Researchers at Japan Tobacco (Osaka, Japan) reported the CB2 selective inverse agonist JTE-907, whose structure is characterized by the presence of a carboxamide group in the 3-position of a quinolone nucleus (66, Fig. 18) (Iwamura et al. 2001) with anti-inflammatory in vivo activity. Naphthyridine derivatives sharing some structural features of JTE-907 were recently reported as cannabinoid receptor ligands with a preference for the CB2 receptor (Ferrarini et al. 2004). 

Katoch-Rouse R, Pavlova OA, Caulder T, Hoffman AF, Mukhin AG, Horti AG (2003) Synthesis, structure-activity relationship, and evaluation of SR141716 analogues development of central cannabinoid receptor ligands with lower lipophUicity. J Med Chem 46 642-645... 

Griffin G, Wray EJ, Rorrer WK, Crocker PJ, Ryan WJ, Saha B, Razdan RK, Martin BR, Abood ME (1999) An investigation into the structural determinants of cannabinoid receptor ligand efficacy. Br J Pharmacol 126 1575-1584... 

Fig. 1. Representative structures ofthe different cannabinoid receptor ligand classes the plant cannabinoid, A -tetrahydrocannabinol the endocannabinoid, arachidonoyl ethanolamide (anandamide) the synthetic pyrazole inverse agonist AM281 and the potent aminoalkylindole agonist AM2233. Both AM281 and AM2233 contain an iodine atom that has been labeled with radioiodine for in vitro and in vivo binding experiments...

R.K. Razdan, V.K. Vemuri, A. Makriyannis, and J.W. Huffman (2009) Cannabinoid Receptor Ligands and Structure-Activity Relationships, Part 1 (ed. P.H. Reggio), Humana Press, New York, pp. 3-94. 

Figure 19.1. Chemical structure of main active ingredient of Cannabis sativa, A9-tetrahydrocannabinol (THC) and the naturally occurring ligand for cannabinoid receptors anandamide (arachidonyl ethanolamide).

The identification of a specific cannabinoid receptor in the brain suggested the existence of a brain cannabinoid ligand. It seemed to us quite unacceptable that the brain will waste its energy to synthesize a receptor (in high concentrations) in order to bind a constituent of a plant. The only reasonable assumption which could be made was that the brain produces a neuronal mediator, a specific compound which binds to and activates the cannabinoid receptor. The plant cannabinoid, J9-THC, by structural coincidence happens to bind to the same receptor. In the late 1980 s, several groups initiated work aimed at the discovery of such a brain constituent. 

The well established use of cannabis over the centuries, the mechanism of the effects of cannabinoids has been unknown until very recently. It was only in 1990 that Matsuda and collaborators identified and cloned a cannabinoid receptor belonging to the G-protein-coupled family of receptors CBl is coupled to G1 to inhibit adenilate cyclase activity and to a partussis-sensitive G protein to regulate Ca2+ currents. Said receptor was found to be mainly located in the brain, in neural cell lines and only to a lesser extent at a peripheral level therefore, in view of its localization, it was called Central Receptor (CBl) (Matsuda et al.. Structure of a cannabinoid receptor and functional expression of the cloned cDNA, Nature, 346 561-564, 1990). The discovery of a receptor led to assume the existence of a specific endogenous ligand. 

Endogenous ligands for the cannabinoid receptor have not yet been identified. Arachidonylethanolamide, a new arachidonic acid derivative named anandamide, was isolated from porcine brain. Its structure was determined by mass spectrometry and nuclear magnetic resonance spectroscopy and was confirmed by synthesis. It inhibits the specific binding of a labelled cannabinoid probe to synaptosomal membranes in a manner typical of competitive ligands, and produces a concentration-dependent inhibition of the electrically-evoked twitch response of the mouse vas deferens, a characteristic effect of psychotropic cannabinoids. Similar compounds were synthesized and their pharmacological properties were investigated. 

Picone RP, Fournier DJ, Makriyannis A (2002) Ligand based structural studies of the CBl cannabinoid receptor. J Pept Res 60 348-356... 

However, studies on structure-activity relationships have revealed that, in addition to classical cannabinoids, other structurally different compounds can also be CB receptor ligands. Thus, the term cannabinoids is now applied to any compound with good affinity for cannabinoid receptors. 

Unfolding Three-Dimensional Energy Maps Statistical tools Applications A 3D QSAR study on the structural requirements for binding to CB1 cannabinoid receptor B 3D QSAR as a tool to design selective ligands... 

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