Formoterol and salmeterol are the first members of a new generation of long-acting beta(2)-adrenoceptor agonists for inhalation. The discovery of the long effect duration of formoterol was made by chance, while the development of salmeterol appeared to follow a purposeful research strategy. 2. Preclinical evaluation predictive of the clinical duration of effect of long-acting bronchodilators is not straightforward. Experiments in vitro may give false positive results, while experiments in vivo may show false negative results. 3. Once the principle of a long duration of effect was established, a number of novel long-acting beta(2)-adrenoceptor agonists of various chemical structure have emerged. 4. There are two alternative models for the explanation of the long duration of effect: the exosite binding explaining the mode of action of salmeterol, and the more general diffusion microkinetic model applicable for both formoterol and salmeterol. 5. Long-acting beta-adrenoceptor agonists with a relatively low efficacy like salmeterol may, under certain circumstances, inhibit competitively the relaxing effect 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-enantiomers, respectively.
