MSU Researchers granted Patent for the invention related to development of anti-obesity compound

A team of researchers from MSU Baroda led by Prof M. R. Yadav, Founder Dean, Faculty of Pharmacy, Dr Prashant R. Murumkar, Asst Professor and Dr Mayank Sharma Research scholar from the same faculty, has been granted a patent for their invention related to the development of a new class of anti-obesity agents that would help to develop drugs which can control the food intake. The project was started 10 years back to invent potent novel anti-obesity compounds.

Many drugs acting on different targets in the body have been reported in literature as anti-obesity agents. Some drugs such as orlistat, lorcaserin, qsymia, contrive and phentermine have been approved by Food and Drug Administration as anti-obesity agents. Some others such as sibutramine and rimonabant were introduced in the market and then withdrawn later on due to their serious side effects. Even the existing approved drugs have also shown significant side effects in the patients. Practically there is no single drug available in the market which could be called as an ideal or safe anti-obesity drug.

The invented compound acts on cannabinoid receptor 1 (CB1R) as CB1R antagonists. CB1 receptors are responsible for performing some vital functions in our body like regulating appetite, pain, emotions. When CB1 receptors are activated, they lead to an urge for eating. If these receptors are blocked or inhibited, the craving for the food decreases. These receptors are located in central nervous system as well as in peripheral tissues. Blocking of central CB1 receptors has many ramifications. Central CB1 receptor blockade plays an important role in the management of obesity but such a blockage produces serious psychiatric side effects.

The main challenge for the researchers was to invent a tight CB1 receptor binding compound which would block the peripheral CB1 receptors only, leaving the central CB1 receptors untouched. Restricting the entry of the drug in the central nervous system was one of the strategies the researchers have worked upon to get rid of the CNS side effects.

The team worked on developing compounds which would have physico-chemical properties which would prevent entry of the compounds in the brain, thus selectively blocking the CB1 receptors present in the peripheral region. Restricting entry of the CB1 receptor antagonists into the brain would lead to minimal or nil CNS side effects.

Computational methods play a vital role in the modern drug discovery process in identifying novel lead molecules, which could be optimized further into clinically useful therapeutic drugs. In the present project high-end computer assisted drug designing techniques were applied for the identification of potent CB1 receptor antagonists. Virtual screening technique on Asinex database (containing more than 4 Lakh compounds) using different filters and tools such as pharmacophore map, 3D-QSAR model, Lipinski's rule of five, CNS scoring and receptor-ligand interaction studies were successfully applied for identifying and designing of novel molecules as anti-obesity agents with minimal or nil side effects.

Further, a strategy was adopted by the team to avoid adverse central effects by designing polar hydrophobic molecules which would fail to penetrate the blood brain barrier (BBB) and remain localized in the peripheral tissues. The synthesized compounds were evaluated for acute hypophagia in rats which showed upto 43 % hypophagic activity. This is the first report in which compounds with phenothiazine scaffold have been reported as peripherally acting CB1 receptor antagonists.

The detailed research work has been reported in a reputed journal 'Scientific Reports" published by Nature publishing group.