Receptor CB

Most relevant for the affinity for A9-THC and analogs to CB-receptors are the phenolic hydroxyl group at C-1, the kind of substitution at C-9, and the properties of the side chain at C-3. Relating to the structure-activity relationships (SAR) between cannabinoids and the CB-receptors, many different modified strucfures of fhis subsfance group were developed and fesfed. The most important variations include variations of the side chain at the olivetolic moiety of the molecules and different substitutions at positions C-11 and C-9. One of the most popular analogous compounds of A9-THC is HU-210 or (-)-trans-ll-OH-A8-THC-DMH, a cannabinoid with a F,l-dimethylheptyl side... 

Cannabinoids are highly lipophilic compounds making bioavailabihty very dependent on the formulation and the mode of administration. Cannabinoid occurrence in the plant is predominantly in the form of the carboxyhc acids, which are pharmacologically totally different and rather unstable, decarboxy-lating over time to their active neutral form. The carboxyhc acids, although not active at the CB receptor, nevertheless add to the overall effect as they possess antibiotic and anti-inflammatory effects. 

Pyridine-, Phenyl-, Pyrimidine- and Pyrazole-based CB] Receptor Antagonists 295... 

Several groups have suggested that the C16-C20 portion of AEA and the C-3 pentyl side chain of (67) may play a similar role in the binding site of the CB receptor [158 161]. To explore this, a number of groups have substituted the C16-C20 pentyl side chain with a l, l -dimethylheptyl chain, a widely... 

IMIDAZOLE-, THIAZOLE-, PYRROLE- AND TRIAZOLE-BASED CB, RECEPTOR ANTAGONISTS... 

The primary psychoactive ingredient in cannabis, A9-tetrahydrocannabinol ( 9- ), affects the brain mainly by activating a specific cannabinoid receptor, CBj. CB receptors are expressed at high levels in many brain regions, and they are primarily... 

CBi and CB2 seem to couple to inhibitory Gj and/or G0 proteins. CBi receptors are known to effect adenylate cyclase, a variety of potassium and calcium currents, and the mitogen-activated protein kinase pathway. CBi receptors have been shown to activate at least six subtypes of Gj and G0 proteins, supporting reports that they effect a wide variety of intracellular signaling systems. In contrast to CB receptors, CB2 receptors do not seem to effect ion currents directly (Breivogel et al., 2001). 

CB-, receptor antagonist, subnanomolar CB-, receptor ligand claimed to be analgesic (Makriannis and Deng, University... 

Rather, they are both produced within neurons and released to flow backward across the synapse to find their receptors, designated as CBi and CBz. There are probably more of these CB receptors for marijuana in the human brain than for any other known neurotransmitter. The great abundance of these receptors and their widespread location gives an indication of importance of the endocannabinoid system in the regulation of the brain s normal functioning. 

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. 

Anandamide was discovered as a high-affinity ligand for CB receptors in 1992 (Devane et al., 1992). Anandamide is produced in response to an increase in intracellular Ca2+ levels or activation of G-protein-coupled receptors (e.g., D2 receptors) (Piomelli, 2003). In mammalian tissues, anandamide is present at concentrations of 1-50 pmol/g (Fig. 4), and can be formed through three distinct biochemical pathways (1) the direct hydrolysis of NAPE by a NAPE-specific phospholipase D (NAPE-PLD) (Okamoto et al., 2005 Wang et al., 2006) (2) the hydrolysis of lyso-NAPE or glycerophospho-anandamide by a specific PLD (Leung et al., 2006 Simon and Cravatt, 2008 Sun et al., 2004) and (3) the hydrolysis of phospho-anandamide by a lipid phosphatase (Liu et al., 2006, 2007) (Fig. 1). 

Anandamide can be hydrolyzed to arachidonic acid and ethanolamine by fatty acid amide hydrolase (FAAH) (Cravatt et al., 1996 Wei et al., 2006) (Fig. 1). FAAH is highly expressed in the brain, where it is expressed at high concentrations in neuronal cell bodies and dendrites that are juxtaposed to axon terminals containing CB receptors. This suggests that anandamide hydrolysis occurs post-synaptically (Piomelli, 2003). 

Highly sensitive targeted lipidomic approaches are rapidly leading to the identification of new analogs of anandamide (Tan et al., 2006). The two major families of lipids that share common chemical structure with anandamide are FAEs and fatty acid amides. Although many of these lipids show no activity at CB receptors, they are known to bind and activate other receptors, such as transient receptor potential vanilloid type-1 (TRPV-1) and the nuclear receptor peroxisome proliferator-activated (PPAR-a). 

Furthermore, a single nucleotide polymorphism of the CB] receptor gene (rs 104935 3) was recendy found to confer an increased risk of antidepressant treatment resistance in female patients with high comorbid anxiety (Domschke... 

There are specific binding sites for cannabinoids, whose endogenous antagonists belong to the class of endocannabinoids. The human organism produces endocan-nabinoids from long-chain polyunsaturated fatty acids, they bind to cannabinoid (CB) receptors and activate them. The CB receptors and endocannabinoids constitute the endocannabinoid system [31]. THC binds to both types of receptors CB1 and CB2. The absence of cannabinoid receptors in the brain stem, the seat of the centers of respiration and other vital functions, explains the low toxicity of cannabinoids. 

Activation of CB receptors by phytocannabinoids such as THC can cause a multitude of effects such as euphoria, anxiety, altered time perception, loss of concentration, and panic attacks. The most commonly researched ones are feeling of well-being, euphoria, and relaxation. THC produces an increase in heart rate, blood pressure, and body temperature (dose-dependent effects). It is also possible to experience dry mouth, increased hunger, and pain reduction. Very high doses of cannabis can cause anxiety, panic, or result in psychotic episodes. 

In several papers the Kunos group has reported observations that may represent a starting point for novel medicinal chemistry research in this area [167, 168], Anandamide (i.v. bolus 4 mg/kg) caused a triphasic blood pressure response, brief hypotension, followed by a transient pressor and then a prolonged depressor phase. The hypotensive effect was not initiated in the CNS, but was due to a presynaptic action that inhibited norepinephrine release from sympathetic nerve terminals in the periphery (heart and vasculature). The inhibitory effect (but not the pressor effect) was antagonized by SR141716A, indicating that this peripheral action was mediated by CB receptors. 

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