We know the side effects of Rimonabant, (see structure) the first selective CB1 receptor blocker to be approved for use anywhere in the world. In Europe, it was indicated for use in conjunction with diet and exercise for patients with a body mass index greater than 30 kg/m², or patients with a BMI greater than 27 kg/m² with associated risk factors, such as type 2 diabetes or dyslipidaemia. In the UK, it was available beginning in July 2006. As of 2008, the drug was available in 56 countries. On October 23, 2008, the European Medicines Agency (EMEA) issued a press release stating that its Committee for Medical Products for Human Use (CHMP) had concluded that the benefits of Acomplia no longer outweighed its risks and subsequently recommended that the product be suspended from the UK market. Sanofi-Aventis later released a press statement stating that the drug had been suspended. Approval of the drug was officially withdrawn by the EMEA on January 16, 2009. But never approved for use in the US because of serious neurological side effects including depression and anxiety.
Now researchers from National Institutes of Health, Bethesda, and Alexandros Makriyannis, at Northeastern University, Boston lead by Dr. George Kunos, have developed a drug (see structure AM6545) that has the same positive effects in mice on levels of glucose and fats in the blood as rimonabant but none of the neurological side effects.
As per researchers claim AM6545 is a non-brain-penetrant neutral CB1R antagonist. First-generationCB1R antagonists, such as rimonabant, are highly lipid soluble and readily penetrate the blood-brain barrier. In order to reduce brain penetrance, we introduced several modifications into the structure of rimonabant. AM6545 is less lipid soluble than rimonabant (estimated partition coefficient [log P], 3.3 vs. 6.4 for rimonabant) but retains high affinity and selectivity for CB1R. In radioligand displacement assays, AM6545 has a KI of 3.3 nM for CB1R, which is similar to that of rimonabant and greater than 100-fold CB1/CB2 selectivity. Unlike rimonabant, AM6545 does not reduce GTPĪ³S binding in mouse brain membranes and is therefore a neutral antagonist.
As per the claim by the researchers, this drug did not cause weight loss or neurological side effects, which rimonabant does, but did have effects on levels of glucose and fats in the blood that should reduce the risk of the serious health consequences of obesity.
The authors therefore hope that this approach of targeting only peripheral CB1R can be translated into the clinic to reduce health risks in obese patients..
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