BETA-AGONISTIC PROPERTIES OF TULOBUTEROL, A NEW BETA-SYMPATHOMIMETIC DRUG, AND ITS EFFECTS ON PULMONARY BETA-ADRENOCEPTOR CHARACTERISTICS

Radioligand binding studies have been developed to determine pharmacologic receptor characteristics in vitro. With this assay, not only the number and dissociation constant (K d ) can be studied, but also the interaction of agonists with the receptor. We used this method to study a new β 2-sympathicomimetic drug, tulobuterol (1-(0-chlorophenyl)-2-butylaminoethanol hydrochloride). Two sets of experiments were performed. One set of experiments investigated the effects of tulobuterol and terbutaline in chronic administration, while the second set compared the β-adrenoceptor-stimulating properties of tulobuterol with terbutaline and salbutamol. The effects of 10 days' administration of tulobuterol and terbutaline on β-adrenergic characteristics in rats were assessed biochemically by means of radioligand binding studies on pulmonary membranes and functionally using isolated tracheal spirals. It was found that: (1) In vivo treatment with both drugs induced a reduction of the number of β-adrenoceptors bound by3H-dihydroalprenolol (3H-DHA); however, tulobuterol also induced an increased affinity for β-adrenoceptor binding. (2) Tulobuterol induced a significant increase in the sensitization of tracheal smooth muscle, facilitating the relaxation of airway smooth muscle. The inhibition of3H-DHA binding with the three drugs was best fit in a two-binding site model, showing high- and low-affinity binding sites. The high-affinity sites had similar K d values for terbutaline and tulobuterol (1.6 × 10-7 and 1.5 × 10-7, respectively). The high-affinity sites for salbutamol had a higher K d value (9.4 × 10-7), suggesting a lower affinity. However, 64.6% and 61.7% of the total binding was inhibited with high affinity by tulobuterol and salbutamol, respectively, while 21.9% was inhibited with high affinity by terbutaline. Therefore, from the ratio of high- and low-affinity binding sites and the K d values of the high-affinity binding sites, tulobuterol appeared the most potent drug with respect to binding to the β 2-adrenoceptor. Also, the coupling of the drug-receptor complex to the adenylate cyclase system and the β 2 selectivity of the drug were established. These β 2-agonistic properties of tulobuterol show the profile of a drug that may prove to be very useful in the management of obstructive lung disease. © 1990 Springer-Verlag New York, Inc.