Cannabinoid 1 receptors (CB1Rs) are mainly located in the brain, and their activation brings about a stimulation appetite and food intake. CB1Rs are also expressed in the peripheral tissues such as adipose tissue, liver, muscle and pancreas. The receptors are directly involved in the appetite-promoting effect as well as in the regulation of energy metabolism, body weight and insulin resistance. Therefore the receptors are the main targets in the development of new drugs for treatment of metabolic disease such as diabetes and obesity.
Rimonabant is the first selective CB1R antagonist. It was developed by Sanofi-Aventis as an anti-obesity agent on the premise that blocking central cannabinoid activity might reduce food intake and body weight. But unfortunately, it induced significant psychiatric side effects, including anxiety, depression, and suicidal ideation. Therefore they had been withdrawn from the market in 2008. However, rimonabant beneficial effects against obesity and metabolic complications are believed to be dissociated from CNS mechanisms involving inhibition of food intake and body weight loss. However it might be dependent on peripheral mechanisms such as reduced lipogenesis and improved insulin resistance. That is why the peripheral CB1R antagonist appears as a new alternative for treating obesity and other associated risks. Thus, unable to pass the blood-brain-barrier, peripheral CB1R antagonists have been developed, and these beneficial peripheral effects could constitute a new therapeutic approach against obesity. Here we demonstrate, using non-brain-penetrant CB1R antagonists, AJ compounds, which are modified from rimonabant.