Agonists cannabinoid

The CBi binding affinity of the hydroxymethyl and carboxyl analogues can be increased by substituting the C3 pentyl side chain for a dimethylheptyl side chain (Table 6.13). 1 l-Hydroxy-l, l -DMH A -THC, HU-210 (165), is an extremely potent cannabinoid agonist that has been widely used as a pharmacological tool [119]. Its ( + ) enantiomer, HU-211 (dexanabinol), which is in clinical development for the treatment of cognitive disorders, does not have high affinity for CBi receptors [120]. 

More recently, the utility of the indole group as a scaffold for cannabinoid agonists has been demonstrated by a number of new patent applications appearing in the literature (286)-(290) [187-190]. Of particular note is compound (286) that is reported to have 18-fold selectivity for the CBi receptor (CBp Ki — 0.08 nM CB2 Ki — 1.44nM). In addition to the indole scaffold, a number of patent applications by AstraZeneca claim indole-like scaffolds such as benzimidazoles (289) [191-193] and azaindoles (290) [194]. Although these compounds bind to both CBi and CB2 receptors, the inventors claim that they may be useful in treating diseases without the associated CNS side effects. 

A number of new scaffolds unrelated to the classical/non-classical cannabinoids and AAIs have been reported in the literature to deliver cannabinoid agonists. 

Bayer [199-203] has claimed in a series of patents a number of aryl sulfonyl esters as cannabinoid agonists for the treatment and prophylaxis of neurodegenerative diseases. Following on from this a number of publications detailing the in vitro and in vivo profiles on two of these compounds, BAY 38-7271 (317) and BAY 59-3074 (318), have been published. 

Novartis AG has filed a patent application on novel naphthalene derivatives as potent cannabinoid agonists, especially at the CBi receptor [208]. One compound was specifically claimed, the naphthalene derivative (319), which exhibited CBi binding with a if value of 15 nM. This compound was also active in an in vivo model of neuropathic pain, reversing hyperalgesia... 

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. 

Standardised preparations of cannabinoid agonists are available for therapeutic use in some countries [238]. Dronabinol (Marinol ), an oral preparation of A -THC (67), is used clinically as an appetite stimulant in AIDS patients and an antiemetic in cancer chemotherapy. A synthetic analogue of (67), nabilone (Cesamet ), (381), is also used to suppress nausea and vomiting in cancer chemotherapy. 

Other therapeutic uses of cannabinoid agonists have been reported. The potential of cannabinoids as a treatment for asthma is supported experimentally. A CBi agonist, (i )-methanandamide (21), inhibited nerve growth factor (NGF)-induced airway hyperresponsiveness in vivo [251]. The antipruritic effect of cannabinoids has been reported, the action being mediated by both CBi and CB2 pathways [252]. Treatment with cannabis extract improved urinary tract symptoms of multiple sclerosis patients significantly in an open-label pilot study [253]. 

Functional interactions between the nicotinic and cannabinoid systems have been proposed (Cohen et al. 2002) and several studies have tested the applicability of these ideas to nicotine discrimination. However cannabinoid agonists acting at cannabinoid CBi and CB2 receptors have failed to generalise with nicotine (Zaniewska et al. 2006). Results with the anandamide uptake and fatty acid amide hydrolase inhibitors AM-404 and URB 597, that elevate brain concentrations of endogenous cannabinoids, were also negative. Furthermore, neither the CBi receptor... 

Turning behavior. Cannabinoid agonists WIN (1-100 ng/mouse), CP-55,940 (0.1-50 ng/mouse), and AEA (0.5-50 ng/mouse), administered unilaterally into the mouse striatum, dose-dependently induced turning... 

Cannabis Cannabis sativa Ag-THC Cannabinoid (agonist) Anandamide... 

III. Effects of Exogenously Administered Cannabinoid Agonists and Antagonists... 

Probably as a consequence of this complex pattern of influence upon different neurotransmitter systems that divergently modulate emotional behavior and mood states, cannabinoid agonists can produce both anxiolytic and anxiogenic effects. 

Although these evidences point at the CBj receptors as an attractive target for the development of antianxiety therapies, the variable effects of exogenous cannabinoid agonists have shifted the interest of pharmacologists to an alternative... 

Martinez-Orgado, J., Fernandez-Frutos, B., Gonzalez, R., Romero, E., Uriguen, L., Romero, J., and Viveros, M. P. (2003). Neuroprotection by the cannabinoid agonist WIN-55212 in an in vivo newborn rat model of acute severe asphyxia. Brain Res. Mol. Brain Res. 114, 132—139. 

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