Cannabinoid antagonist development

Barth F, Rinaldi-Carmona M (1999) The development of cannabinoid antagonists. Curr Med Chem 6 745-755... 

It is clear that, as Barth and Rinaldi-Carmona pointed out in their review on the development of the cannabinoid antagonist, [45] that the millennial therapeutic use of C. sativa has led modem medical science to the research of new analgesic compounds based on cannabinoid antagonists. 

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... 

Our development of [123I]AM281, an antagonist radioligand for brain cannabinoid receptors, has allowed us to image this receptor for the first time in vivo. Ex vivo autoradiographic experiments have been conducted in rodents, and SPECT studies have been conducted in baboons. Research... 

Conversely, food intake and body weight are reduced by the selective cannabinoid CBl antagonist SR 141716. Tolerance developed to the anorectic effect of SR 141716 within 5 days of chronic treatment, but body weight remained low throughout 14 days of treatment. In contrast, chronic THC treatment (15 days) suppresses intake of food and water (Drewnowski and Grinker 1978). This effect is of short duration, with... 

These impressive advances in biology have not been paralleled by developments in the therapeutic area. The psychotropic effects of d9-THC, and the stigma attached to cannabis as an abused drug, has resulted in a pronounced lack of enthusiasm within the pharmaceutical companies. However, the recent development of cannabinoids that do not cause a psychotropic effect, and yet have therapeutically important features (HU-211, for example), the discovery of antagonists and of cannabinoids that bind preferentially to the peripheral CB2, may bring about enhanced pharmaceutical research. 

Some studies have suggested that there may be links between the development of dependence to cannabinoids and to opiates (42). Some of the behavioral signs of rimonabant-induced withdrawal in THC-treated rats can be mimicked by the opiate antagonist naloxone (43). Conversely, the withdrawal syndrome precipitated by naloxone in morphine-dependent mice can be partly relieved by THC (44) or endocannabinoids (45). Rats treated chronically with the cannabinoid WIN55212-2 became sensitized to the behavioral effects of heroin (46). Such interactions can also be demonstrated acutely. Synergy between cannabinoids and opiate analgesics has been described above. THC also facilitated the antinociceptive effects of RB 101, an inhibitor of enkephalin inactivation, and acute administration of THC caused... 

Cannabis is known to stimulate appetite, and promote food intake ( the munchies ). The identification of cannabinoid (CB1) receptors in the brain allowed the development of selective antagonist compounds such as Ri-monabant, which was found to suppresses food intake in laboratory animals (Colombo et al. 1998). Clinical trials have shown it to be significantly more effective than placebo in assisting overweight patients lose weight (see Chapter 8). 

---