Comparison of enantiomers of SPFF, a novel β2-adrenoceptor agonist, in bronchodilating effect in guinea pigs

Abstract

Previous study on racemic SPFF [2-(4-amino-3-chloro-5-trifluomethyl-phenyl) -2-tert-butylamino-ethanol hydrochloride], a novel β2- adrenoceptor agonist, has validated that it is a potent, long-acting bronchodilator with relative higher β2-adrenoceptor selectivity. On the basis of this study, we compared the pharmacological properties of SPFF and its enantiomers ((-)-SPFF and (+)-SPFF) in guinea pigs taking isoprenaline or salbutamol (SAB) as referenced drugs. For the relaxation of both normal and precontracted trachea strips in vitro, (-)-SPFF was found more potent than (±)-SPFF or (+)-SPFF. Moreover, we confirmed that the bronchodilator effect of (-)- and (+)-enantiomers were due to activation of the β2-adrenoceptor because this effect was antagonized by a specific β2-adrenoceptor antagonist, ICI-118551, with similar pA2 values to those of (±)-SPFF. Radioligand binding assay revealed that affinity of (-)-enantiomer to β2-adrenoceptor was 6 and 164 fold greater than that of (±)- and (+)-SPFF, respectively. In addition, isomeric difference of overall selectivity between (-)-SPFF and (+)-SPFF was 10.7 fold for lung versus atria. (-)-SPFF displayed almost the same protective effect against bronchospasm induced by histamine-acetylcholine aerosol in conscious guinea pigs as (±)-SPFF did. However, the latent time of (+)-SPFF (1mg·kg-1) was significantly shorter than that of (±)- and (-)-SPFF at the same doses. Finally, in the inhibition of histamine-induced increase of pulmonary resistance (RL) in anesthetized guinea pigs, (-)-SPFF was 1.3 and 3.5 times more potent than (±)- and (+)-SPFF. Correspondingly, in inhibiting the decrease of pulmonary compliance (CL) , the potencies of (-)- and (+)-enantiomers were approximately equivalent to that of (±)-SPFF. Furthermore, a study on the long-lasting action of the test drugs had shown that the effects of (-)-SPFF (30 μg·kg-1), (±)-SPFF (30 μg·kg-1) and (+)-SPFF (100 μg·kg-1) in inhibiting the increase of RL all lasted for 4 h. Nevertheless, the effects of (-)- and (+)-enantiomers were slightly lower 4h after intraduodenal administration in inhibiting the decrease of CL. In conclusion, (-)-SPFF may be beneficial for the treatment of asthma because of its more potent efficacy and higher adrenoceptor affinity than (±)- or (+)-SPFF. © 2008 Pharmaceutical Society of Japan.