New anti-obesity research into Melanocortin 4 and Marijuana THC affecting CB1R receptors
Date: May 11, 2006
Title: “Discovering new anti-obesity therapeutics”
Speaker’s Name and Affiliation: Tung Fong, PhD, Merck Research Laboratories
Dr. Fong, of Merck Research Laboratories, presented an overview of how new pharmacological solution for the treatment of obesity are discovered. Long-term energy restriction without pharmacological intervention is not possible for most people.
In developing new anti-obesity drugs, the first step is to determine appropriate targets for the drugs that will produce the best long-term outcomes. Energy balance can be affected by alterations in central and peripheral nervous systems, but also by convergent inputs on both of these systems. Central nervous system targets, such as MC4R and CB1R are of particular interest because they have ramifications for both energy intake and expenditure.
MC4R is melanocortin 4 receptor system
When designing new MC4R targets, there are some chemical challenges that need to be overcome, including the efficacy and selectivity of the molecule, whether the molecule penetrates the blood-brain barrier, and the toxicity and safety of the drug.
Because of it’s involvement with the central nervous system, MC4R is a potential target for new anti-obesity therapies. The frequency of the melanocortin-4 receptor (MC4R) gene variation in the morbidly obese population is between 1-5%. The receptors are found in a variety of locations in the CNS, where they are primarily involved with energy metabolism and feeding.
MT-II is a non-selective MC4R agonist that reduces food intake and increases metabolic rate compared to vehicle in animal models. These, and other MC4R agonists, work by inhibiting food intake in wild type animals, but fail to do so in MC4R knock-outs.
CB1R, marijuana, endocannabanoids
In addition to the melanocortin 4 receptor system, the endocannabinoid system has recently been implicated in feeding control, and studies suggest that THC, the active ingredient in marijuana, increases appetite and feeding. THC is an agonist of the CB1R receptor, which has been identified in the cortex, amygdala, hippocampus, and hypothalamus. Binding of THC to this receptor acts by decreasing release of several neurotransmitters, including GABA and glutamate.
Administration of leptin has been shown to decrease production of endocannabanoids (Di Marzo et al, 2001). Further, CB1R knock-out animals have reduced DIO, increased insulin sensitivity and metabolic rate, and decreased RQ.
Q. Are the baseline intakes similar under vehicle conditions?
Q. The aromatic membranes of the molecules suggest that they are soluble in lipids. Could you tag or make them, or make them into a lysosome, to increase their solubility?
A. Probably not, but it hasn’t been well investigated.
Q. How do you avoid digestion when these agents are given orally?
A. The small molecule compounds do not have peptide bonds or ester bonds that would be targeted by GI digestive enzymes.
Q. How are the compounds given to animals?
A. Oral gavage.
Q. So do you postulate that they got into the brain?
Q. If you do the same with diet (as with pharmaceutical agents) you will see the same type of reduction in body weight, followed by a rebound?
Q. Have you considered trying this in animals that are sated?
A. Not yet, but it’s certainly worth doing.
Q. If you have a heterozygous receptor, how does that translate information into the number of genes.
A. You will have a normal distribution of receptors, but just less total number of them.
Q. Is the thyroid function normal in your animals?
A. We haven’t measured that yet.
Q. Have you looked at anti-seizure activity in animals given rimonabant?
A. Rimonabant does not have anti-seizure activity that I know of.
Q. Do you measure body composition on your animals?
A. Yes. It appears that most of the weight loss can be accounted for by fat loss.
Q. Do you get a more pronounced effect in the hypothalamus?
A. The compound is distributed in relatively the same areas throughout the brain.
Q. Have you seen any side effects (to rimonabant) in rodents that are similar to those reported in humans?
A. We have seen the opposite effects in rodents. Rimonabant has antidepressant effects in rodents.
Q. What about anxiety?
A. The data are conflicting and it depends on how you measure anxiety in the animals.
Q. Have you tested any of these drugs for a longer length of time?
A. We have looked as long as four weeks in our animals. Most of the weight is lost in the first week or week and a half, and after that, weight is maintained.
Q. Is drug treatment an appropriate strategy for long-term, in your opinion?
A. We believe that a combination of approaches offers the best results.
Q. Have you considered looking at ghrelin antagonisits?
A. We probably will in the future.
Q. What about the increase in dropout rate in the rimonabant trial? What do you make of that?
A. We are not sure if the 50% dropout rate might be a difference between responders and non-responders. For people who actually take the drug long-term, they seem to maintain their weight loss.
Q. Is there any evidence that histamines are related to obesity?
A. Yes. Some published reports state that some histamine agonists might decrease body weight, but we need to understand the receptors better.
Q. Do you have any evidence that animals are getting sick in your studies with rimonabant?
A. Studies suggest that rimonabant works by inhibiting intake of chow, sugar solutions, etc. But, we don’t have any evidence that animals are sick in these trials.
Q. What about treating obesity as a chronic disease? We need to have longer trials for this?
A. I believe that if you discontinue any treatment, animals (humans) will rebound.