SOME PHARMACODYNAMIC ASPECTS ON LONG-ACTING BETA-ADRENOCEPTOR AGONISTS

1. Formoterol and salmeterol are the first members of a new generation of long acting beta(2)-adrenoceptor agonists for inhalation. The disc overy of the long effect duration of formoterol was made by chance, wh ile the development of salmeterol appeared to follow a purposeful rese arch strategy. 2. Preclinical evaluation predictive of the clinical du ration of effect of long acting bronchodilators is not straightforward . Experiments in vitro may give false positive results, while experime nts in vivo may show false negative results. 3. Once the principle of a long duration of effect was established, a number of novel long-acti ng beta(2)-adrenoceptor agonists of various chemical structure have em erged. 4. There are two alternative models for the explanation of the long duration of effect: the exosite binding explaining the mode of ac tion of salmeterol, and the more general diffusion microkinetic model applicable for both formoterol and salmeterol. 5. Long-acting beta-adr enoceptor agonists with a relatively low efficacy like salmeterol may, under certain circumstances, inhibit competitively the relaxing effec t of agonists with higher efficacy like formoterol and salbutamol. 6. Like all other beta(2)-adrenoceptor agonists in current clinical use, formoterol and salmeterol comprise racemic mixtures. Only the RR- and R-enantiomers are pharmacologically active. The experimental compounds TA-2005 and picumeterol have been developed as pure RR- and R-enantio mers, respectively.