Researchers from Columbia University, New York, NY, and the University of Wisconsin-Milwaukee are diligently working to radically change the way asthma is treated, especially in children, by developing a drug that will replace inhalers and the aerosolized steroids they deliver, according to a trial published in the April 25 issue of Molecular Pharmaceutics.
This drug, taken orally as a pill, may not only alleviate problems with inhaler use—which children often do not use properly—but the side effects that are a concern with long-term steroid use as well.
Specifically, they are working on redesigning a drug compound initially created by James Cook, of the Milwaukee Institute for Drug Discovery, UWM, to calm anxiety without dangerous side effects. One of the NIH-funded programs Cook and colleagues are working on is focused on the design and synthesis of the γ-amino butyric acid type A (GABAA)-ergic benzodiazepine receptor modulator ligands for the treatment of anxiety disorders via enhancement of the neurotransmitter GABA in the brain.
Charles Emala, MD, anesthesiologist, Columbia University Medical Center, found that GABA receptors are also present in the lungs, and requested some compounds from Cook’s lab for work he was doing on lung physiology. Dr. Emala’s studies led to the question of whether GABA receptors could be harnessed to relax the inflammation and constriction caused by asthma in the smooth muscles of the lungs.
“Emala’s email was like a Christmas present,” said Dr. Cook, a UWM distinguished professor of chemistry who holds 47 patents or patent applications for drug compounds. “In 2008, our lab had made compounds that might work for this purpose. But lacking biology, they were just put on a shelf.”
Two years’ into their research, Dr. Emala and fellow researchers have confirmed that these compounds can reduce airway inflammation as well as limit blood-brain barrier exposure. Specifically, they have found that certain GABA receptors—such as GABAA—can be targeted with these compounds.
In a murine model of asthma, they found that phenolic α4β3γ2 GABAAR selective compound 1 and acidic α5β3γ2 selective GABAAR-positive allosteric modulator compound 2 relaxed airway smooth muscle ex vivo and diminished airway hyperresponsiveness. In addition, these researchers also observed the following:
- Compound 2 relaxed acetylcholine contracted human tracheal airway smooth muscle strips.
- Both compounds had anti-inflammatory properties, with oral treatment effecting a decrease in eosinophils in bronchoalveolar lavage fluid in ovalbumin-sensitized and challenged mice.
- Compound 1 reduced the number of lung CD4+ T lymphocytes and directly modulated their transmembrane currents by acting on GABAARs.
- Both compounds had long plasma half-lives of up to 15 hours, oral availability, and very low brain distribution.
“We would revolutionize the field if we could replace the inhaler,” said Douglas Stafford, director of the Milwaukee Institute for Drug Discovery (MIDD). “These are critical design factors that are just as important as drug efficacy.”