New Class Of Molecules As Histamine-3 Receptor (H3R) Modulators: A New Lead In Clinical Management Of Obesity

If we don’t somehow stem the tide of childhood obesity, we’re going to have a huge problem. —Lance Armstrong

Comprehensive lifestyle management like diet, physical exercise, and behavior modification are the best ways to treat obesity. An alternative to this is drug-based therapy. Although not preferred or prescribed until lifestyle modifications fall short in achieving that goal, pharmacotherapy provides an opportunity for the obese population to achieve weight loss and to reduce the incidence of associated health hazards like cardiovascular disease, diabetes, cancer, and stroke.


Only a limited number of drugs are currently available that have either serious side effect profiles or modest efficacy for the long-term treatment of obesity. Most of the anti-obesity drugs function by altering the patient’s appetite or by reducing fat absorption. Currently, orlistat is the only drug approved by the FDA for long-term use. Under these circumstances, a novel histamine 3 receptor (H3R) agonist (as shown in Figure 1) was identified recently by a drug discovery research group in CSIR-CDRI Lucknow, India, which could lead to new candidate drugs for the management of obesity.

Credit: Ajay Kumar Srivastava

A systematic exploration of β-lactams and pyrrolidinone derivatives by utilizing an efficient chemistry could result in exciting findings. Most of the molecules were prepared in a single flask chemical transformation often termed as one-pot protocols. Four components were reacted in methanol at room temperature, and the Ugi reaction was monitored by thin layer chromatography (TLC). Once the first reaction was complete, reagents for the second transformation were added followed by monitoring of the reaction by TLC. The products were isolated by filtration, and complicated chromatographic procedures were not required. This type of chemical transformation reduces the amount of chemical waste and thus is useful for developing sustainable chemical processes.

The biological screening of these compounds revealed that they are highly specific to H3R and did not interfere with related isoforms such as H1R, H2R, and H4R. A careful investigation of structural features was performed to understand the pharmacophore that is required to design molecules with improved efficacy and safety.

Figure 1. Most potent compound of the series. Credit: Ajay K. Srivastava

In the next stage of our research, we evaluated the efficacy of the most active molecule in mice. It was also interesting to note that our molecule stimulates a hypophagic response in mice reflecting the reduction in food intake. The computational analysis of physicochemical and pharmacokinetic properties of the identified actives suggest that these molecules might possess good bioavailability and permeability, which are important parameters for developing a candidate drug.


Additionally, we checked the possible covalent interaction of these molecules with other proteins by performing luciferase assay. Further studies to optimize and develop candidate drugs from the identified actives are currently underway.

These findings are described in the article entitled, Identification of novel β-lactams and pyrrolidinone derivatives as selective Histamine-3 receptor (H3R) modulators as possible anti-obesity agents, recently published in the European Journal of Medicinal Chemistry. This work was conducted bythe teams of Dr. Ajay K. Srivastava, Dr. Prem N. Yadav and Dr. Muhammad Wahajuddin from CSIR-Central Drug Research Institute (CSIR-CDRI), Lucknow, India.



Detection On The Go For A Common Viral Pathogen

Human noroviruses are a leading cause of gastroenteritis globally and inflict a considerable public health burden. The viruses are easily […]

A Blue Moon and Lunar Eclipse Will Happen For The First Time in 150 Years This Month

An incredibly rare event will occur on this January 31. The end of the month will see a lunar eclipse […]

The Influence Of The Resting Of Veld Combined With Game On Previously Overgrazed Vegetation Of The Nama-Karoo

Land managers in the Nama-karoo are constantly faced with the daunting task of managing their land in an economically and […]

Chaperone Protein AdDJSKI Of A.diogoi Potentiates Biotic As Well As Abiotic Stress Tolerance In Tobacco

Arachis diogoi, a wild diploid species related to the cultivated peanut, is resistant to the late leaf spot pathogen Phaeoisariopsis […]

The World’s Biggest Killer: Pollution Kills Over 9 Million People Every Year

As more and more research is done, the harm done by pollution becomes ever clearer. A new report recently published […]

Jupiter Rings: Does Jupiter Have Rings?

Yes, Jupiter has 4 sets of rings made up of dust and small pieces of rocks. Jupiters 4 rings are […]

What Does pH Stand For And Mean?

pH stands for potential hydrogen with the “p” meaning potential and the “H” standing for hydrogen. The pH scale is […]

Science Trends is a popular source of science news and education around the world. We cover everything from solar power cell technology to climate change to cancer research. We help hundreds of thousands of people every month learn about the world we live in and the latest scientific breakthroughs. Want to know more?