Comparison of Enantiomers of SPFF, a Novel .BETA.2-Adrenoceptor Agonist, in Bronchodilating Effect in Guinea Pigs

Abstract

b 2 -Adrenoceptor agonists, the most effective bronchodilator, have long been widely used in symptomatic therapy of asthma. A variety of b 2 -adrenoceptor agonists are currently available, such as salbutamol, terbutaline, salmeterol, formoterol and procaterol. The majority of b 2 -adrenoceptor agonists possess chiral center(s) (asymmetric carbon atom) in their structures; therefore, they exist as pair(s) of enantiomers.1) Based on the conformational stereochemistry and pharmacokinetic parameters, enantiomers can vary greatly in their pharmacological effects on target tissue(s).2) Except for levalbuterol, most available b 2 -adrenoceptor agonists are a racemic mixture of equimolar (R)-and (S)-enantiomer. Against this background, separation of enantiomers is a practice increasing in popularity, since a single optical isomer may represent a safer and more efficacious alternative than its corresponding racemate.3) 2-(4-Amino-3-chloro-5-trifluomethyl-phenyl)-2-tert-butylamino-ethanol hydrochloride (SPFF) is synthesized and exploited by the drug synthesis laboratory of Shenyang Pharmaceutical University as a novel b 2 -adrenoceptor agonist. Gan et al. 4) has found that bronchodilator effects of racemic SPFF on isolated guinea pig trachea strips with or without precontraction of bronchoconstrictors (histamine and acetylcholine) were more potent than isoprenaline. Moreover, it was confirmed that the bronchodilator effect of racemic SPFF was due to the activation of b 2 -adrenoceptor because this effect was easily antagonized by a specific b 2 -adrenoceptor antagonist, ICI-118551 (pA 2 ϭ8.90Ϯ0.01). Furthermore, the positive chronotropic effect of SPFF on isolatd guinea pig left atria (pD 2 ϭ5.41Ϯ0.38) was much weaker than that of isoprenaline (pD 2 ϭ8.75Ϯ0.24). A radioligand binding experiment using guinea pig lung and cardiac ventricle as b 2 and b 1 adrenoceptor sources, respectively, also demonstrated that racemic SPFF possesses high affinity and selectivity to b 2 -adrenoceptor. The protective effect of racemic SPFF on bronchospasm induced by bronchoconstrictor aerosol in guinea pig in vivo was 6 times more potent than that of sulbutamol, and the Konzett and Rösler experiment performed in anesthetized rabbits showed that racemic SPFF exerted action of longer duration than sulbutamol did. In the present study we compared the pharmacological effects of racemic SPFF with its individual enantiomers on bronchodilating action and potency in guinea pigs. MATERIALS AND METHODS Chemicals and Drugs

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