An abandoned weight-loss drug gets a makeover

Remember the experimental weight-loss drug rimonabant, touted as a potential “miracle pill” that could help obese smokers kick the habit, lose weight and keep it off for two years? Marketed in Europe as Acomplia, the drug made it well into the U.S. Food and Drug Administration’s approval process before it was linked in 2008 to a doubling of depression risk in those taking it. The drug ended up withdrawn from the European market and pulled from FDA consideration, another failed medication on the ash heap of obesity treatments.

Or maybe not. A new study finds that a structural modification that prevents the active molecule from entering the brain might give a new lease on life to the the whole idea of promoting weight loss by manipulating the body’s cannibinoid-receptor system.

In a study published in the journal Cell Metabolism, scientists gave obese rats a chemical variant of the drug that gave rimonabant its ability to bring about weight loss. The resulting agent, called JD5037, “robustly reduces food intake, body weight and adiposity” and was “devoid of behavioral effects,” the researchers reported.

It did so by blocking the body’s receptors for endocannibinoids -- messenger chemicals that play a role in metabolism and energy use as well as in mood, pain perception and satiety. While many of the body’s cannibinoid receptors reside in the brain (hence their role in mood), some also operate in such organs as the liver and in fat -- which, in the obese, plays a powerful role in sending signals that say, in effect, “feed me.”

But since scientists suspect that blocking cannabinoid receptors in the brain may wreak havoc on mood, the key here was to find a way to block cannabinoid receptors throughout the body but not in the brain’s cortical regions. This is what they did, modifying a cannabinoid blocker called SLV319 so that it could not penetrate the blood-brain barrier.

Chubby rats put through a maze on the SLV319 became anxious and showed disrupted sleep patterns. But the rats given the structurally modified JD5037 suffered no such side effects, even as they lost weight. The study found that blocking cannabinoids in the body’s “periphery” increased the body’s sensitivity to the hormone leptin, which in turn increases the burning of fat for fuel and suppresses appetite.

In rats as well as people, obesity gradually drives down the body’s sensitivity to leptin. Scientists believe this may be the mechanism that evolved to help us maintain or regain our stores of fat. That may work well for animals that must survive drought and starvation. But in modern times, when tasty calories aren’t hard to come by for humans, it’s what makes us hold onto or regain weight, even when we try to lose it through calorie restriction and exercise.

After seven to 28 days on JD5037, obese rats were not only slim, their circulating leptin levels were similar to those of lean, healthy mice, and their insulin resistance and fatty livers resolved.

By sensitizing the body to leptin of its own making, the authors wrote, the new chemical entity “may not only promote weight loss, but could help maintain it.”