Some pharmacodynamic aspects on long-acting beta-adrenoceptor agonists

Area of Science:

• Pharmacology
• Respiratory Medicine
• Drug Discovery

Background:

• Formoterol and salmeterol are novel long-acting inhaled beta(2)-adrenoceptor agonists.
• The discovery of formoterol's long duration was serendipitous, while salmeterol's development was strategic.
• Preclinical assessment of long-acting bronchodilator duration is challenging, with potential for inaccurate in vitro and in vivo results.

Purpose of the Study:

• To explore the mechanisms behind the prolonged duration of action of novel long-acting beta(2)-adrenoceptor agonists.
• To compare different models explaining the long-acting effect, including exosite binding and diffusion microkinetics.
• To discuss the implications of drug efficacy and enantiomeric composition on bronchodilator activity.

Main Methods:

• Review of existing literature on long-acting beta(2)-adrenoceptor agonists.
• Analysis of proposed models for long duration of effect (exosite binding, diffusion microkinetics).
• Comparison of pharmacological properties, including efficacy and enantiomeric forms.

Main Results:

• Two models explain the long duration of effect: exosite binding (salmeterol) and diffusion microkinetics (formoterol, salmeterol).
• Lower efficacy agonists like salmeterol can competitively inhibit higher efficacy agonists (formoterol, salbutamol).
• Current drugs are racemic mixtures; enantiomerically pure compounds (TA-2005, picumeterol) are under development.

Conclusions:

• The development of long-acting beta(2)-adrenoceptor agonists has advanced significantly.
• Understanding the mechanisms of action and potential drug interactions is crucial for optimizing therapy.
• Enantiomeric separation offers potential for developing more targeted and effective bronchodilators.