- Drugs that stimulate β2-adrenergic receptors (β2AR) can facilitate relaxation of the muscles in the airways of the lungs and relieve the airway constriction seen in asthma and other lung conditions.
- Prolonged use of these drugs is associated with reduced therapeutic efficacy and possible worsening of asthma symptoms..
- Using a combination of computer simulations and laboratory experiments, a recent study has identified new molecules that selectively enhance the therapeutic effects of drugs that stimulate β2-adrenergic receptors without affecting other pathways.
Until recently, most drug development efforts have focused on molecules that bind to a receptor to activate or inhibit intracellular signaling pathways within cells.
However, those molecules that bind to the primary site on the target receptor can cause significant adverse effects by binding to other receptors that share a similar structure.
A new approach involves the use of
These allosteric modulators do not directly affect signaling pathways on their own, but only enhance or inhibit the effects of agonist binding at the primary receptor site. Therefore, allosteric modulators are less likely to produce side effects.
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Asthma drugs and decreased effectiveness
Excessive use of drugs that activate β2RA for the treatment of asthma and other obstructive lung conditions is associated with decreased therapeutic efficacy.
Arecent studypublished in the magazinePNASidentified allosteric modulators that selectively increase 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 relaxation of airway muscles.
The researchers say that the use of these allosteric modulators may allow the use of drugs that activate β2AR at lower concentrations, limiting the decline in therapeutic efficacy over time.
Deepak Deshpande, PhD, study author and professor at Thomas Jefferson University in Philadelphia, said, "In this study, we developed a new set of compounds that increased beneficial signaling (involving Gs proteins) and function (mild muscle relaxation and bronchodilation of the respiratory tract ) . ).”
"The main implication of this study is that we have established a unique way to improve the therapeutic efficacy of β-agonists," he said.Today's medical news."Considering the widespread use of β-agonists in the clinical treatment of bronchoconstriction associated with multiple lung diseases, the findings of our study pave the way for the development of next-generation β-agonists with improved therapeutic efficacy."
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respiratory conditions likeasmaand chronic obstructive pulmonary disease (COPD) are characterized by narrowing of the pulmonary airways and breathing difficulties.
Contraction of the smooth or involuntary muscles lining the airways of the lungs contributes to the narrowing of the airways.
neurotransmitters and hormones
Drugs that selectively stimulate the
Due to its selective activity on β2AR expressed by airway smooth muscles, treatment with these agonists produces dilation of the pulmonary airway muscles without producing side effects such as increased heart rate caused by β activation1ARKANSAS.
Embora tal b2AR agonists are effective in the short term in the prevention and treatment of asthma and other obstructive pulmonary diseases, their chronic use is associated with a decrease in their therapeutic effect and, in some cases, with the worsening of asthma symptoms.
Union of a β2The AR receptor agonist results in activation of the Gs protein, which mediates the effects of these drugs on smooth muscle relaxation. However, binding of β-agonists2RA also leads to activation of G protein-coupled receptor kinases and β-arrestins.
Activation of G protein kinases and β-arrestin receptors can lead to β desensitization2AR, which involves a decrease in the ability of β2AR agonists to activate Gs protein. In addition, β-arrestins can also reduce β expression2AR on the surface of smooth muscle cells. This may limit the ability of β2AR agonists to induce airway smooth muscle relaxation and relieve asthma symptoms.
In addition, stimulation of β2AR can also activate signaling pathways through β-arrestin in addition to Gs protein. Activation of β-arrestin signaling is associated with worsening of asthma symptoms.
Although there are some drugs, such asphosphodiesterase inhibitors, which can enhance Gs signaling, these compounds tend to have limited efficacy and significant adverse effects.
Therefore, there is a need for effective treatments that can relieve asthma symptoms in the long term.
Allosteric modulators bind to a different site than the agonist and can influence receptor activity only in the presence of the agonist.
Activation of β-arrestin after β2AR stimulation depends on the concentration and duration of exposure to β2AR agonist. Therefore, allosteric modulators that can selectively amplify β2Gs signaling induced by AR agonists may allow the use of β2AR agonists at lower concentrations without activating the β-arrestin pathway. This may allow the use of β2AR agonists for an extended period without compromising their therapeutic effect.
The present study used a computational approach to identify molecules that could bind to β2AR at an allosteric site. Allosteric modulators enhance or suppress the agonist response by inducing a conformational change in the receptor, which influences the duration or strength of the agonist-receptor interaction.
The researchers first used a computational method that allowed them to map the three-dimensional structure of β2AR protein in a stable conformation that was intermediate between its active agonist bound state and its 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 create a list of 100 potential candidates.
These compounds were tested in human embryonic kidney cells engineered to express β2AR and human airway smooth muscle cells grown in tissue culture to reduce five molecules that could enhance Gs activation. The researchers focused in particular on one of the five compounds that induced the greatest increase in Gs signaling.
These allosteric modulators were specific for β2AR, potentiating β2Gs signaling induced by AR agonists. In contrast, these allosteric modulators did not affect the response to β1AR activation. Furthermore, these modulators did not influence β-arrestin activation after β stimulation.2- ARKANSAS.
In particular, a trial using airway muscle tissue cultures showed that the use of the allosteric modulator in combination with a β2The AR agonist helped relieve airway smooth muscle cell contraction to a greater extent than the agonist alone. Furthermore, the use of allosteric modulators in combination with β2The AR agonist also produced increased airway dilation in lung sections obtained from mice and humans.
The present study evaluated 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 effectiveness and examine their therapeutic effects in animal models.
"Our goal is to generate preclinical data on these compounds so that we can move forward with clinical trials on these compounds," said Deshpande.
dr. Fady Youssefsaid a pulmonologist, internist and critical care specialist at MemorialCare Long Beach Medical Center in Long Beach, CA.today's medical news“It is quite intriguing to see evidence that may have some potential to explain patients' reports of a diminished response to their inhalers. While the cell line data can be quite compelling, I'd like to see it validated in animals or humans. If the findings hold, consideration should be given to the need for treatment strategies that take into account the intended receptor desensitization or down-regulation."