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

Previous study on racemic SPFF [2-(4-amino-3-chloro-5-ti-ifluomethyl-phenyl)-2-tert-butylamino-ethanol hydrochloride], a novel beta(2)-drenoceptor agonist, has validated that it is a potent, long-acting bronchodilator with relative higher beta(2)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 beta(2)-adrenoceptor because this effect was antagonized by a specific beta(2)-adrenoceptor antagonist, ICI-118551, with similar pA(2) values to those of (+/-)-SPFF. Radioligand binding assay revealed that affinity of (-)-enantiomer to beta(2)-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 (1 mg.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 (R-L) in anesthetized guinea pigs, (-)-SPFF was 1.3 and 3.5 times more potent than and (+/-)-SPFE Correspondingly, in inhibiting the decrease of pulmonary compliance (C-L), 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 mu g.kg(-1)), (+/-)-SPFF (30 mu g.kg(-1)) and (+)-SPFF (100 mu g.kg(-1)) in inhibiting the increase of R-L all lasted for 4 h. Nevertheless, the effects of (-)- and (+)-enantiomers were slightly lower 4 h after intraduodenal administration in inhibiting the decrease of C-L. In conclusion, (-)-SPFF may be beneficial for the treatment of asthma because of its more potent efficacy and higher adrenoceptor affinity than (+/-)- or (+)-SPFF.