New possibilities for the beta-adrenoceptor agonist bronchodilator drugs.

The pharmacological basis of the selectivity of bronchodilator beta-adrenoceptor agonists is discussed. Functional selectivity depends on both drug-related and tissue-related factors. Extensive enlargement of the beta-adrenoceptor agonist molecules permits interaction with hypothetical exoreceptor sites. A soft drug inhaled for local effects and which subsequently is inactivated by biotransformation, may give a minimum of systemic side effects. Conversely, a prodrug which requires metabolic activation offers new possibilities to alter the pharmacokinetic properties of a beta-adrenoceptor agonist. Several new compounds with interesting properties are presently subject to clinical trials.

The effect of D2343 in transmurally stimulated rabbit isthmus muscle.

In in vitro experiments spirally cut isthmic preparations from oestrogenized rabbits have been contracted by transmural stimulation. The beta 2-agonistic and alpha 1-antagonistic drug D2343 (for chemical structure, see fig. 1 in Olsson et al. 1984) inhibits the evoked contractions in a concentration related fashion with 50% effect at 9.6 X 10(-6) mol/l. The alpha 1-antagonist prazosin has an inhibiting action in the same concentration range (EC50 = 14.0 X 10(-6) mol/l). To inhibit the contractile response to the same degree by the beta 2-agonist terbutaline the concentration has to be greater than 10(-3) mol/l. From received results the beta (beta 2)-adrenoceptor mediated effects seem to be of minor importance compared to the alpha (alpha 1)-receptor dominance in the isthmus muscle during oestrus.

The use of two different pharmacological principles to inhibit a cholinergic bronchospasm in guinea pig.

The ability of inhaled atropine and clonidine to inhibit a bronchospasm produced by injected acetylcholine or by vagal stimulation, was studied in anaesthetized guinea pigs. Vagally mediated airway constriction was restrained in a concentration-related fashion by inhaled clonidine and reached nearly 100% inhibition (EC50 = 2 X 10(-5) mol/l in the nebulizer). Atropine expressed initially about the same level of spasmolytic effect but only a final prevention of 60% was possible to reach with this drug. On the contrary, inhaled atropine was able to produce a complete inhibition (EC50 = 2 X 10(-6) mol/l) when the bronchoconstriction was elicited by exogenous acetylcholine. This type of spasm was also to some degree inhibited by clonidine.

The effects in myometrial preparations of D2343, a beta 2-adrenoceptor agonist possessing alpha 1-receptor blocking qualities.

D2343 is a compound with about the same beta 2-adrenoceptor-agonist effect as terbutaline and exhibiting in addition an alpha 1-receptor inhibitory activity. D2343 has been compared to the beta 2-agonist terbutaline on oestrogenized uterine preparations from rat and rabbit (in vitro and in vivo) and in myometrial strips from homo. Generally, D2343 has shown an ability to relax the uterine muscles to the same degree as terbutaline or even more, especially when the two drugs were compared in vitro in preparations from rabbit and rat.

New lipophilic terbutaline ester prodrugs with long effect duration.

Two new lipophilic terbutaline ester prodrugs - the biscarbamate bambuterol (pINN) and the cascade ester D 2438 - have been designed with the goal to achieve enhanced absorption and high hydrolytic stability during first-pass in order to prolong the effect duration of the parent compound. Bambuterol, the bis-N,N-dimethyl-carbamate of terbutaline, displays improved hydrolytic stability, partly by inhibition of its own hydrolysis, and has been shown to survive first-pass hydrolysis in the dog to a high degree. Bambuterol per se is inactive; however, after oral administration to guinea-pigs, the ED50 value for protection from histamine-induced bronchospasm is similar to that of terbutaline. Moreover, the terbutaline plasma level-time profile after oral doses of bambuterol in dogs is significantly prolonged. The cascade ester of terbutaline (D 2438), derived from p-pivaloyloxybenzoic acid, was designed to undergo first-pass hydrolysis and conjugation at the p-pivaloyloxybenzoic acid moiety; i. e. distal from the active resorcinol moiety in terbutaline. The prodrug itself is active in the isolated guinea-pig trachea and displays prolonged effect duration both after inhalation in guinea-pigs and after oral administration in dogs. The cascade ester prodrug (D 2438) has a somewhat shorter effect duration than bambuterol in these species.

Some problems encountered in the evaluation of new bronchodilating beta-adrenoceptor agonists.

A series of phenylethanolamine derivatives were examined with respect to their bronchospasmolytic effect and their ability to depress the contractions of the soleus muscle in cat and guinea-pig. One group of compounds including D2343 (1-(4-hydroxyphenyl)-2-[1,1-dimethyl-3-(2-methoxyphenyl) propylamino]-ethanol HCl), a new beta 2-adrenoceptor agonist, appeared to be more effective in combating bronchospasm induced by histamine than in depressing the contractions of the soleus muscle in anaesthetized cat. This difference disappeared when serotonin was used to induce bronchospasm. Terbutaline antagonized histamine and serotonin equally well. Experiments in vivo and in vitro with guinea-pigs gave ambiguous results. Slowly developing effects was a common feature of the compounds showing the apparent effect separation. None of the available beta-adrenoceptor agonists appears to distinguish between the adrenoceptors in the airway smooth muscle mediating bronchial relaxation and those in the skeletal muscle associated with tremor.

A new beta 2-adrenoceptor agonist with alpha 1-adrenoceptor blocking properties.

The phenylethanolamine D2343 exhibits a dualistic adrenoceptormediated effect, i.e, a beta-agonistic effect combined with an alpha-antagonistic one. Tracheal smooth muscles and heart preparations were used to gauge the agonistic effect of adrenergic beta-receptors. Rabbit aorta and rat vas deferens were used to determine the alpha-adrenoceptor blocking activity. The beta-adrenoceptor activity of D2343 was classified as beta 2-type with about the same efficacy as the beta 2-selective terbutaline on tracheal muscle. The effect on isolated heart preparations was greater than that produced by terbutaline. The alpha-receptor blocking capacity was directed against the alpha 1-receptor type and was of nearly the same potency as for phentolamine.

Effects of beta-adrenoceptor agonists on airway smooth muscle and on slow-contracting skeletal muscle: in vitro and in vivo results compared.

Ten beta-adrenoceptor agonists were examined with respect to a) relaxation of pilocarpine-contracted trachea and depression of contractions of the soleus muscle of the guinea-pig in vitro and b) counteraction of histamine-induced bronchospasm and depression of contractions of the soleus muscle of the cat in vivo. There was a close correlation between the results obtained in vitro and results obtained on the corresponding tissues in vivo in spite of the different species used. A close correlation was also observed between effects on airway smooth muscle and on the soleus muscle contractions in vitro as well as in vivo for all compounds examined.