Breathe in, breathe out. Many individuals take it for granted to be able to do this without a second thought. After all, breathing is a rather routine behavior. However, for many people worldwide, it presents more of a problem. Millions of people are affected by asthma, a lung disease that makes breathing difficult due to inflammation and narrowing of a person’s airways. The disease can be caused by a variety of factors, including genetics, allergies, respiratory infections, or irritants in the environment. The American Lung Association has an animation found here which effectively explains the condition.
Asthma is a chronic disease, which means it lasts over a person’s lifetime and affects a person’s life every single day. People with asthma are more sensitive to irritants, or “triggers.” Currently there is no cure, although with proper treatment a person with asthma can lead a normal, healthy life. The two current options for treatment are addressing the long term effects through consistent medication or the short term symptoms on a case by case basis. So what medications are out there? While there are different brands and different chemical formulas, what they all have in common is the presence of the beta-agonist compound, which will be explained in detail throughout this blog.
What are beta2 andergenic agonists?
In most asthma medications, there is one active chemical that soothes the signature symptom: a tightened and restricted throat. This chemical, the most common of asthma medications, is called the beta2 andergenic agonist. What this chemical does is opens up calcium-activated potassium channels in nerve cells, thus hyperpolarizing the airway smooth muscle cells.The hyperpolarization, which leads to the inhibition of any action potentials, relaxes the smooth muscles and widens the bronchi.
There are two different types of beta agonists for different medical purposes. The first is the short-acting, which work quickly, usually within 3 to 5 minutes, and only last 4 to 6 hours. This type of medication is often a reliever medication for symptoms that require fast relief and do not last a long time, such as breathlessness. On the opposite side of the spectrum there are the long-acting beta-agonists which take longer to start working, however last up to 12 hours. Such drugs are considered maintenance drugs, treating asthma as a chronic illness rather than a set of symptoms to treat whenever they arise.
The way these processes are carried out within the body can be explained using chemical kinetics, and the rate that the reactions are being carried out depending on the dose and the chemical formula of the different compounds. The short-acting drugs have a much faster rate of reaction than the long-acting drugs, meaning either the concentration is varied between the two, or the physical and chemical properties of the beta-agonist alter the rate of the reaction.
Mechanism and Crystal Structure of Beta2-Adrenergic Receptors
Before studying in detail the chemical properties Beta2-adrenergic agonists possesses, it is important to understand the interrelation of the agonist to a receptor, and the subsequent processes that are carried out as a result. The British Pharmacological Society gives an overview of how the agonists work overall.
Without its receptor, there is no need for substances such as beta2 adrenergic agonists to exist, for the surface molecule receptor is the stage upon which these agonists show their talents. In other words, just as a substrate and an enzyme work together in order to carry out chemical reactions, the agonist gives the receptor the directions it needs to undergo cellular processes. In this way, beta2-adrenergic agonists such as norepinephrine (noradrenaline) and epinephrine (adrenaline) have objectives, this objective being to bind with the receptor.
This is where the Beta2-adrenergic receptor (also known as ADRB2) comes in, working as an adrenoceptor in the category of G protein coupled receptors (GPCRs). GPCRs are the destinations of catecholamines (organic compounds with an amine and catechol, here the norepinephrine and epinephrine). The protein receptor set of GPCRs are sensitive to the presence of extracellular molecules and in response initiate signal transduction. (Signal transduction pathways are composed of two parts, the first being the receptor-agonist interaction, and then a secondary emissary signals for the cell to start certain processes). The binding of the beta2-adrenergic agonist will activate the SNS, or sympathetic nervous system, which deals with acute stress response (fight-or-flight instinct) and regulation of homeostasis.
A primary component in the function of ADRB2 is its structure, with seven helices that stretch over individual membranes, and external structures that form disulfide bonds (covalent bond) to reach a stable form.
Connections to Organic Chemistry
Naturally the human body produces many beta-adrenergic-agonists itself, including the physiologic molecules norepinephrine and epinephrine pictured to the left. The agonists work by binding to beta-adrenergic receptor complexes which activates a chain of reactions ending in the phosphorylation of CREB (cAMP response element binding protein) which stimulates the transcription of regulatory genes. When beta-agonists specifically stimulate receptors in the lungs they cause relaxation and dilation of the airways. Because of the efficacy of this method of treating asthma, much of the biomedical community has synthesized many organic molecules that have the ability to be helpful to asthma patients. Chemists in the field of organic chemistry are profusely involved in synthesizing simpler and more effective molecules for the activation of beta-receptors in the lungs, which aids in the movement towards better asthma treatments overall.
As a final note on beta2-agonists, these synthesized molecules do have certain limitations to keep in mind. Because they are not produced by the human body itself, the human body does not have the necessary mechanisms to regulate them as it would with molecules that are produced by the body. This has possibly been linked to a few skeletal diseases, and the video here highlights some of the concerns with using beta-agonists overall.