EP4 receptor as a new target for bronchodilator therapy

BACKGROUND: Asthma and chronic obstructive pulmonary disease are airway inflammatory diseases characterised by airflow obstruction. Currently approved bronchodilators such as long-acting β(2) adrenoceptor agonists are the mainstay treatments but often fail to relieve symptoms of chronic obstructive pulmonary disease and severe asthma and safety concerns have been raised over long-term use. The aim of the study was to identify the receptor involved in prostaglandin E(2) (PGE(2))-induced relaxation in guinea pig, murine, monkey, rat and human airways in vitro. METHODS: Using an extensive range of pharmacological tools, the relaxant potential of PGE(2) and selective agonists for the EP(1–4) receptors in the presence and absence of selective antagonists in guinea pig, murine, monkey, rat and human isolated airways was investigated. RESULTS: In agreement with previous studies, it was found that the EP(2) receptor mediates PGE(2)-induced relaxation of guinea pig, murine and monkey trachea and that the EP(4) receptor mediates PGE(2)-induced relaxation of the rat trachea. These data have been confirmed in murine airways from EP(2) receptor-deficient mice (Ptger2). In contrast to previous publications, a role for the EP(4) receptor in relaxant responses in human airways in vitro was found. Relaxant activity of AH13205 (EP(2) agonist) was also demonstrated in guinea pig but not human airway tissue, which may explain its failure in clinical studies. CONCLUSION: Identification of the receptor mediating PGE(2)-induced relaxation represents a key step in developing a novel bronchodilator therapy. These data explain the lack of bronchodilator activity observed with selective EP(2) receptor agonists in clinical studies

Picumeterol: Dissociation of improvement in lung function and reduction of airways hyperresponsiveness in asthmatics

Aims The new potent and selective beta(2)-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. FEV(1)) 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. lit vitro, picumeterol was found have intrinsic activity lower than the other beta(2)-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