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Experts say asthma medications can lose their effectiveness over time. svetikd/Getty Images
  • Drugs that stimulate the β2-adrenergic receptors (β2AR) can facilitate the relaxation of lung airway muscles and alleviate airway constriction observed in asthma and other lung conditions.
  • Prolonged use of these drugs is associated with a decline in their therapeutic efficacy and the potential worsening of asthma symptoms.
  • Using a combination of computational simulations and laboratory experiments, a recent study identified new molecules that selectively enhance the therapeutic effects of drugs that stimulate the β2-adrenergic receptors without affecting other pathways.

Until recently, most efforts to develop drugs have focused on molecules that bind to a receptor to activate or inhibit intracellular signaling pathways inside the cells.

However, these molecules that bind to the primary site on the target receptor can lead to significant adverse effects upon binding to other receptors that share a similar structure.

A novel approach involves the use of allosteric modulators, which are molecules that adhere to a site on a protein, such as a receptor, to modulate the response of the receptor to molecules that have stimulatory or inhibitory actions at the primary site of the receptor.

Such allosteric modulators do not directly impact signaling pathways on their own but only enhance or inhibit the effects of the agonist binding at the primary site of the receptors. Thus, allosteric modulators are less likely to produce side effects.

The overuse of drugs that activate β2AR for the treatment of asthma and other obstructive lung conditions is associated with a decline in therapeutic efficacy.

A recent study published in the journal PNAS identified allosteric modulators that selectively enhanced signaling pathways in airway muscle cells involved in mediating the therapeutic effects of β2-adrenergic drugs.

Consistently, these allosteric modulators also amplified the ability of β2-adrenergic drugs to induce the relaxation of airway muscles.

Researchers say the use of these allosteric modulators could allow the use of drugs that activate β2AR at lower concentrations, thus limiting the decline in therapeutic efficacy over time.

Deepak Deshpande, PhD, the study’s author and a professor at Thomas Jefferson University in Philadelphia, said, “In this study, we developed a novel set of compounds that augmented beneficial signaling (involving Gs proteins) and function (relaxation of smooth muscle and bronchodilation of airways).”

“The main implication of this study is that we established a unique way of improving the therapeutic efficacy of β-agonists,” he told Medical News Today. “Considering the extensive use of β-agonists in the clinical management of bronchoconstriction associated with multiple lung diseases, our study findings pave the way for the development of next-gen β-agonists with improved therapeutic efficacy.”

Respiratory conditions such as asthma and chronic obstructive pulmonary disease (COPD) are characterized by the narrowing of the lung airways and breathing difficulties.

The contraction of smooth or involuntary muscles that line the lung airways contributes to the narrowing of the airways.

The neurotransmitters and hormones adrenaline and noradrenaline are known to cause the relaxation of the airway’s smooth muscles by binding and activating β-adrenergic receptors. β1– and β2-adrenergic receptors are the two major types of β-adrenergic receptors.

Drugs that selectively stimulate the β2-adrenergic receptors (β2ARs) expressed on the surface of airway muscle cells are the first line of treatment for the symptoms associated with asthma and other obstructive lung diseases. Such compounds that stimulate a receptor and mimic the effects of a natural compound are referred to as agonists.

Due to their selective activity on the β2AR expressed by smooth airway muscles, treatment with these agonists produces dilation of the lung airway muscles without producing side effects, such as an elevated heart rate caused by the activation of β1AR.

Although such β2AR agonists are effective in the short term in the prevention and treatment of asthma and other obstructive lung diseases, their chronic use is associated with a decline in their therapeutic effect and, in some cases, the worsening of asthma symptoms.

Binding of a β2AR agonist to the receptor results in the activation of the Gs protein, which mediates the effects of these drugs on smooth muscle relaxation. However, the binding of the agonists to the β2AR also leads to the activation of G protein-coupled receptor kinases and β-arrestins.

The activation of G protein receptor kinases and β-arrestins can lead to the desensitization of the β2AR, which involves a decline in the ability of β2AR agonists to activate Gs protein. In addition, β-arrestins can also reduce the expression of the β2AR on the surface of smooth muscle cells. This can limit the ability of β2AR agonists to induce airway smooth muscle relaxation and alleviate the symptoms of asthma.

Moreover, the stimulation of the β2AR can also activate signaling pathways via β-arrestin in addition to the Gs protein. The activation of the β-arrestin signaling is associated with the worsening of asthma symptoms.

Although there are some drugs, such as phosphodiesterase inhibitors, that can augment Gs signaling, these compounds tend to have limited efficacy and significant adverse effects.

Thus, there is a need for effective therapeutics that can alleviate asthma symptoms over the long term.

Allosteric modulators are compounds that bind to the receptor to enhance or dampen the activity of an agonist (or antagonist) at the receptor.

Allosteric modulators bind to a site that is distinct from the one for the agonist and can influence the activity of the receptor only in the presence of the agonist.

The activation of β-arrestin after β2AR stimulation is dependent on the concentration and duration of exposure to the β2AR agonist. Thus, allosteric modulators that can selectively amplify β2AR agonist-induced Gs signaling could potentially allow the use of β2AR agonists at lower concentrations without activating the β-arrestin pathway. This could allow the use of β2AR agonists over a long duration without compromising their therapeutic effect.

The present study used a computational approach to identify molecules that could bind to the β2AR at an allosteric site. Allosteric modulators enhance or suppress the response to the agonist by inducing a change in the conformation of the receptor, thus influencing the duration or strength of the interaction between the agonist and the receptor.

The researchers first used a computational method that allowed them to map the three-dimensional structure of the β2AR protein in a stable conformation that was intermediate between its active agonist-bound state and inactive unbound form. The researchers then identified a potential binding site for allosteric modulators based on this structure.

The researchers initially used computational methods to screen 1,000 compounds and arrive at a list of 100 potential candidates.

These compounds were tested on human embryonic kidney cells engineered to express the β2AR and human airway smooth muscle cells grown in tissue culture to narrow down five molecules that could enhance Gs activation. The researchers particularly focused on one of the five compounds that induced the largest increase in Gs signaling.

These allosteric modulators were specific for the β2AR, enhancing β2AR agonist-induced Gs signaling. In contrast, these allosteric modulators did not impact the response to β1AR activation. Moreover, these modulators did not influence the activation of β-arrestin upon the stimulation of β2-AR.

Notably, an assay using tissue cultures of airway muscle cells showed that the use of the allosteric modulator in combination with a β2AR, agonist helped to alleviate the contraction of airway smooth muscle cells to a greater extent than the agonist alone. In addition, the use of the allosteric modulators in combination with the β2AR agonist also produced a greater dilation of airways in lung slices obtained from mice and humans.

The present study assessed the therapeutic potential of these allosteric modulators using tissue cultures of airway muscle cells and cultured lung slices obtained from humans and mice. In their subsequent work, the researchers intend to further optimize these compounds to improve their efficacy and examine their therapeutic effects in animal models.

“Our goal is to generate the pre-clinical data on these compounds such that we can move forward with clinical trials on these compounds,” Deshpande said.

Dr. Fady Youssef, a pulmonologist, internist, and critical care specialist at MemorialCare Long Beach Medical Center in Long Beach, CA, told Medical News Today that “It is quite intriguing seeing evidence that possibly can hold some potential to explain patients’ reports of a waning response to their inhalers. While cell line data can be quite compelling, I would like to see it validated in animal or human subjects. If the findings do hold, one would consider the need for treatment strategies that would factor in desensitization or downregulation of the intended receptor.”