Cannabinoid receptors compounds

Group of compounds which naturally occur in the hemp plant, Cannabis saiiva. Most of them are unsoluble in water. The most abundant cannabinoids are A9--tetrahydrocannabinol (THC), its precursor cannabidiol and cannabinol, which is formed spontaneously from THC. Cannabinoids exert their effects through G-protein coupled cannabinoid receptors (CBi/CB2). 

The best studied of the endocarmabinoids are anandamide (A -arachidonyl-ethanolamine, AEA)(1) and 2-arachidonylglycerol (2-AG)(2). Anandamide was first identified from porcine brain extracts by Devane and co-workers in 1992 [13], while 2-AG was first reported in 1995 to have been isolated from canine gut [14] and rat brain [15]. More recently, noladin ether (2-arachidonyl-glyceryl ether, 2-AGE)(3) [16], virodhamine (D-arachidonyl-ethanolamine)(4) [17] and A-arachidonyl-dopamine (NADA)(5) [18] were proposed as endogenous ligands for the cannabinoid receptors. In a subsequent publication, the authors failed to detect noladin ether in mammalian brains and questioned the relevance of this compound as an endocarmabinoid [19]. Anandamide, noladin ether and NADA have functional selectivity for CBi receptors, virodhamine is CB2 selective and 2-AG is essentially non-selective. 

In addition, Novartis filed a patent application on a series of quinazolines as cannabinoid agonists [209]. Compound (320) is one of the two compounds specifically claimed and exhibited CBi and CB2 binding with if values of 34 and 11 nM, respectively. It was shown to be a full agonist at the CBi receptor with an EC50 of 132nM (no functional data for the CB2 receptor). Compound (320) was also active in the neuropathic pain model described above with an ED50 of 0.5mg/kg after oral dosing. 

Vogel Z, Barg R, Levy D, Saya E Eleldman, Mechoulam R. Anandamide, a brain endogenous compound, interacts specifically with cannabinoid receptors and inhibits adenylate cyclase. J Neurochem 1993 61 352-355. 

Figure 1 Structures of representatives of classes of compounds that blind to cannabinoid receptors. 

The cellular actions of cannabinoids clearly support the proposal that the cannabinoid receptor is inhibitory and, consequently, reduces the firing rate of target neurons. However, this is not wholly confirmed by electrophysiological measurements, which suggest that cannabinoid compounds can stimulate neurons in the hippocampus. This apparent discrepancy may be due to the ability of cannabinoids to inhibit the release of an inhibitory substance in the hippocampus and, thus, produce a net excitation. 

A number of pharmaceutical companies are working to develop drugs that will block the marijuana high sought by the world s estimated 144 million regular marijuana users. In 1988, researchers identified the receptors in the brain to which the marijuana molecule attaches. Named Cannabinoid Receptor l (CBl), it became the site of intensive scientific research, subsequently leading to the discovery that the brain naturally produces several compounds that fit the CBl receptors. One of these natural compounds was named anandamide from ananda, the Sanskrit word for bliss. ... 

The cannabinoid-type psychoactive principles of marijuana Cannabis sativa L.), have been of interest to pharmacologists for many years. The biological characterization of the major euphoriant principle, (—j-A - wr-tetrahydrocannabinol (THC) (20), has led to an understanding of the molecular mechanisms of these compounds, and ultimately enabled the characterization of the cannabinoid receptor This... 

Our research group expected that additional polyunsaturated fatty acid ethanolamides may be present in the brain. We also identified in porcine brain another two putative endocannabinoids, namely homo-y-linoleoylethanolamide (K = 53.4 5-5 nM) and 7,10,13,16-docosatetraenoylethanolamide (K = 34.4 3.2 nM). The isolation of these two compounds as constituents of porcine brain that bind to the cannabinoid receptor demonstrated that anandamide is not the sole representative of this class of potential mediators. 

Later, we described the isolation of a second type of cannabinoid receptor ligand, 2-arachidonoyl glycerol (2-AG) (K = 5-85 0.12 xM), an ester isolated from canine gut. " This was the first putative endogenous cannabinoid receptor ligand isolated from a peripheral tissue. Later, Sugiura et al isolated independently this compound from brain. 

The endocannabinoids are accompanied in the brain and other tissues by cannabinoid-like compounds, which however do not bind to the cannabinoid receptors. They are saturated and mono- or diunsaturated congeners, which may affect the metabolism and the function of the endocannabinoids... 

Analogous to the discovery of the endogenous opiates and opiate receptors, the discovery of cannabinoid receptors in 1988 suggested the presence of endogenous cannabimimetic compounds. In 1992 anandamine—the ethanolamide of arachidonic acid was purified from porcine brain and shown to behave... 

Cannabis sativa plants contain at least 400 different compounds, of which as many as 60 are structurally related to 5 -tetrahydrocannabinol (5 -THC), the primary psychoactive constituent of cannabis. When cannabis is smoked, hundreds of additional compounds are produced by pyrolysis, which may contribute to both acute and chronic effects (Abood and Martin, 1992). The central nervous system actions of canna-binoids are mediated primarily through the CBj receptor. A second type of cannabinoid receptor, termed the CB2 receptor, is distributed primarily in the periphery (Gifford et ah, 1999). Activation of central cannabinoid receptors modulates neurotransmitter release at... 

The first identified cannabinoid receptor subtype, CB was cloned and demonstrated to have an amino acid sequence consistent with a tertiary structure typical of the seven transmembrane-spanning proteins that are coupled to G proteins. In addition to being found in the central nervous system, mRNA for CB has also been identified in testes. The central nervous system responses to cannabinoid compounds are believed to be mediated exclusively by CB, inasmuch as CB2 transcripts could not be found in brain tissue by either Northern analysis or in situ hybridization studies. CBj transduces signals in response to central-nervous-system-active constituents of C. sativa as well as synthetic bicyclic and tricyclic cannabinoid analogs, aminoalkylindole, and eicosanoid cannabimimetic compounds. CB is coupled to G, to inhibit adenylate cyclase activity and to a pertussis-sensitive G protein to regulate Ca2+ currents. 

Cannabinoids may also cause effects via mechanisms distinct from the cannabinoid receptor pathways. The most extensively investigated compound is (+)-HU 211, a synthetic cannabinoid with a stereochemistry opposite to that present in the naturally occurring compounds. It does not produce THC-type effects in animals and shows insignificant binding to the CB, receptor. However, HU 211 blocks A-methyl-n-aspartate (NMDA) receptors and calcium uptake through the NMDA-receptor-ion channel in primary cell cultures. HU 211 is a potent blocker of NMDA-induced tremor, seizures, and lethality in mice. It may therefore prove useful as a nonpsychoactive drug that protects against NMDA-receptor-mediated neurotoxicity. This is supported by the potent attenuation of NMDA-receptor-mediator neurotoxicity in cell cultures by HU 211. 

A cannabinoid is a type of chemical compound concentrated in the resin of the cannabis plant. THC is the only cannabinoid that is highly psychoactive and present in large amounts in cannabis. Until recently, there has been little information on precisely how THC acts on the brain, which cells are affected by THC, or even what general areas of the brain are most affected by it. All this changed in the 1980s and 1990s with the discovery of specific cannabinoid receptors—Cannabinoid receptor 1 (CB1) and Cannabinoid receptor 2 (CB2). 

One compound that is not an NSAID but is often lumped into this group is acetaminophen (Tylenol, A.154) (Figure A.43). Acetaminophen is both an analgesic and suppresses fever but has no effect on inflammation and blood clotting. Acetaminophen also has less impact on the stomach lining than NSAIDs. Acetaminophen is believed to act both by COX inhibition as well as other pain response pathways. Unlike NSAIDs, acetaminophen acts on cannabinoid receptors. 

Cannabinoids may share at least some common neuronal mechanisms with opioid compounds. Studies of intracellular events associated with ligand binding to either cannabinoid or opiate receptors indicate that these receptors are linked via G proteins to the production of cAMP. Certain studies have also indicated that there may be some interaction between cannabinoid binding sites and opiate receptors in the reward pathway. In addition, there is increasing evidence that cannabinoids interact with opiate systems involved in the perception of pain. In fact, cannabinoids clearly produce analgesic effects in both experimental animals and humans, and of all the potential clinical uses of cannabinoids, the mediation of analgesia has received the most attention. Some evidence also indicates that the cannabinoid receptor system is an analgesic system. 

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