title: Comparison of enantiomers of SPFF, a novel beta2-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 beta2-adrenoceptor agonist, has validated that it is a potent, long-acting bronchodilator with relative higher beta2-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 beta2-adrenoceptor because this effect was antagonized by a specific beta2-adrenoceptor antagonist, ICI-118551, with similar pA2 values to those of (+/-)-SPFF. Radioligand binding assay revealed that affinity of (-)-enantiomer to beta2-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 (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 microg.kg(-1)), (+/-)-SPFF (30 microg.kg(-1)) and (+)-SPFF (100 microg.kg(-1)) in inhibiting the increase of RL all lasted for 4 h. Nevertheless, the effects of (-)- and (+)-enantiomers were slightly lower 4 h 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.
authors.affiliation: Department of Pharmacology, School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, No.103 Wenhua Rd., Shenyang 110016, PR China.
authors.forename: Zhihui
authors.initials: Z
authors.lastname: Hao
authors.forename: Yuyang
authors.initials: Y
authors.lastname: Zhang
authors.forename: Li
authors.initials: L
authors.lastname: Pan
authors.forename: Xing
authors.initials: X
authors.lastname: Su
authors.forename: Maosheng
authors.initials: M
authors.lastname: Cheng
authors.forename: Minwei
authors.initials: M
authors.lastname: Wang
authors.forename: Houde
authors.initials: H
authors.lastname: Zhao
authors.forename: Yingliang
authors.initials: Y
authors.lastname: Wu
mesh_terms: D000109:Acetylcholine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000403:Airway Resistance / Q000187:drug effects; D000818:Animals; D001986:Bronchial Spasm / Q000139:chemically induced / Q000517:prevention & control; D001993:Bronchodilator Agents / Q000494:pharmacology*; D002082:Butylamines / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D006168:Guinea Pigs; D006633:Histamine Antagonists / Q000494:pharmacology; D066298:In Vitro Techniques; D008170:Lung Compliance / Q000187:drug effects; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D011412:Propanolamines / Q000494:pharmacology; D013237:Stereoisomerism; D014132:Trachea / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: C477926:2-(4-amino-3-chloro-5-trifluomethyl-phenyl)-2-tert-butylamino-ethanol chloride; D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D001993:Bronchodilator Agents; D002082:Butylamines; D006633:Histamine Antagonists; D011412:Propanolamines; D014665:Vasodilator Agents; C026777:ICI 118551; D000109:Acetylcholine