Comparison of Enantiomers of SPFF, a Novel β_2-Adrenoceptor Agonist, in Bronchodilating Effect in Guinea Pigs(Pharmacology)

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Previous study on racemic SPFF [2-(4-amino-3-chloro-5-trifluomethyl-phenyl)-2-tert-butylamino-ethanol hydrochloride], a novel β_2-adrenoceptor agonist, has validated that it is a potent, long-acting bronchodilator with relative higher β_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 β_2-adrenoceptor because this effect was antagonized by a specific β_2-adrenoceptor antagonist, ICI-118551, with similar pA_2 values to those of (±)-SPFF. Radioligand binding assay revealed that affinity of (-)-enantiomer to β_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 (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 (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 μg・kg^<-1>), (±)-SPFF (30 μg・kg^<-1>) and (+)-SPFF (100 μg・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.
公益社団法人日本薬学会の論文
2008-05-01

Comparison of Enantiomers of SPFF, a Novel β_2-Adrenoceptor Agonist, in Bronchodilating Effect in Guinea Pigs(Pharmacology)

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