Picumeterol

Aims The new potent and selective β2‐adrenoceptor agonist, GR 114297A (picumeterol) is the R‐enantiomer of the racemic form, GR 63411B. Picumeterol has been shown to produce long‐lasting relaxation of airways smooth muscle both in vitro and in vivo. We assessed the intrinsic activity of picumeterol by increasing intracellular levels of c‐AMP and compared this with isoprenaline and salbutamol.Methods In human atopic asthmatics, we have investigated the duration of action and efficacy of picumeterol and GR 63411B with regard to improvement in resting lung function (i.e. FEV1 ) and airways responsiveness (i.e. PC20 ) to methacholine (MCh). The study design consists of two clinical parts each for one drug. Different asthmatics participated in the two studies, seven in the first part and eight in the second part. In human bronchial smooth muscle cells in vitro, we have investigated the intrinsic activity of picumeterol in increasing intracellular levels of cyclic AMP and compared it with isoprenaline and salbutamol.Results In vivo, both drugs caused bronchodilatation with similar potency, but, their effects were short‐lasting. Despite their bronchodilator activity, neither drug improved PC20, when compared with placebo. In vitro, picumeterol was found have intrinsic activity lower than the other β2‐adrenoceptor agonists tested.Conclusions In the clinical studies, the bronchodilator potencies of picumeterol and GR 63411B were similar. However, both drugs were short‐acting, which is at odds with their activity in vitro. Our data suggest that these compounds display dissociation between bronchodilator activity and protection against MCh‐induced bronchoconstriction. These findings may be explained by low intrinsic activity and need further conformation.

1. 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.