Cannabinoid agonists cannabinoids

Sanofi-Synthelabo researchers discovered pyrazole 53 and analogs to have potent Cannabinoid receptor-1 (CB-1) antagonist/inverse agonist activity and have progressed 53 into development for treatment of obesity and alcohol dependence. The synthesis of 53 was accomplished by heating the diketone sodium salt 51 with the aryl hydrazine hydrochloride in acetic acid to provide the intermediate 52, which was further derivatized... 

Bouaboula, M., Perrachon, S., Milligan, L., Canatt, X., Rinaldi-Carmona, M., Portier, M., Barth, F., Calandra, B., Pecceu, F., Lupker, J., Maffrand, J.-P., Le Fur, G., and Casellas, P. (1997). A selective inverse agonist for central cannabinoid receptor inhibits mitogen-activated protein kinase activation stimulated by insulin or insulin-like growth factor. J. Biol. Ckem. 272 22330-22339. 

Endogenous cannabinoids Endogenous agonists of cannabinoid receptors... 

Braida D, Pozzi M, Cavallini R, et al Intracerebral self-administration of the cannabinoid receptor agonist CP 55,940 in the rat interaction with the opioid system. EurJ Pharmacol 413 227-234, 2001... 

Martellotta MC, Cossu G, Fattore L, et al Self-administration of the cannabinoid receptor agonist WIN 55,212—2 in drug-naive mice. Neuroscience 85 327—330, 1998... 

A -THC, the main psychoactive component of cannabis, is a moderately potent partial agonist of the CBi and CB2 receptors, while cannabidiol has little affinity for either receptor (Table 6.7). The term classical cannabinoids is used to describe cannabinoid receptor modulators structurally related to (67), which have a tricyclic dibenzopyran core. While several other structural types of cannabinoid receptor modulators have been discovered in recent years, the classical cannabinoids are still by far the most extensively studied group in terms of SAR and pharmacology. 

Tables 6.8-6.11 illustrate the wide range of C3 side-chain modified A -THC analogues that have been reported in the literature, together with associated in vitro and in vivo data. The affinity of classical cannabinoid analogues for the CBi receptor has been shown to correlate with depression of spontaneous activity and the production of antinociception, hypothermia and catalepsy in mice, and with psychomimetic activity in humans [93]. However, in some cases, there were unexplained differences between the observed trends in binding affinity and the trends in activity in mouse behavioural models. This may point to differences in efficacy among full agonists, partial agonists and antagonists/inverse agonists, or may reflect differences in in vivo metabolism or blood-brain barrier penetration or a combination of these factors.

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]. 

A fourth important pharmacophoric element was established for the non-classical cannabinoid series in the form of a southern aliphatic hydroxyl group. Addition of this group to (192) resulted in the high-affinity CBi and CB2 receptor full agonist CP 55,940 (193) [129, 133], the tritiated form of which was used to first demonstrate specific cannabinoid binding sites in brain tissue [134]. Its enantiomer, CP 56,667 (194) has lower affinity for the CBi receptor (Table 6.17). 

As outlined earlier, anandamide was the first among the endogenous cannabinoid receptor agonists to be identified. It exhibits higher binding affinity for the CBi receptor Ki — 89 nM) than for the CB2 receptor (il = 371 nM) [81]. Anandamide has typical cannabinoid activities including decreased spontaneous motor activity, immobility and production of hypothermia and analgesia [147, 148]. However, this action in vivo is of shorter duration than... 

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]. 

Martin and co-workers [196] have also published on the discovery and SAR of pyrazole cannabinoids as described in the CBi agonist section. The analogues were tested for CBi receptor binding affinity and in a battery of in... 

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