The overall objective of this project is to gain a better understanding of the molecular portions of trimetoquinol (TMQ) that are necessary for highly potent and selective action on pharmacological receptors in pulmonary and cardiovascular systems, in vitro and in vivo. This application outlines the synthesis of (1) Alpha-benzyl substituted analogs (2) piperidine analogs (3) aromatic substituted fluorine analogs and (4) a carbostyril analog of TMQ. Potent Beta2-selective analogs of TMQ will be resolved for biological studies. These proposed analogs will take advantage of recent findings as to requirements for highly potent and selective Beta2-adrenoceptor agonists with a long duration of action. The primary aims of the biological studies will be to pharmacologically and biochemically characterize the organ selectivity and comparative potency of the newly synthesized analogs of TMQ in Beta-adrenoceptor mediated responses. These compounds will be tested for their (1) potency as agonists or antagonists in tracheal, atrial and lung parenchymal preparations from guinea pigs and (2) effects on the immunological release of physiological mediators of bronchoconstriction in allergen-sensitized guinea pig lung tissue. Subsequent experiments will be initiated with promising TMQ analogs to establish the efficacy and organ selectivity in vivo. These in vivo studies will involve the measurement of drug-induced aerodynamic changes in pulmonary function and cardiovascular responses in conscious guinea pigs and rats. Of a lower priority, the interaction of TMQ analogs with Alpha-adrenoceptor- and thromboxane A2-mediated constriction of vascular (rat aorta) and bronchial smooth muscle (parenchyma) tissues will be characterized. The goal of this work is to synthesize and characterize a new series of TMQ analogs which preferentially interact and show a high degree of specificity for Beta-adrenoceptor systems in lung tissue. The development of highly selective Beta2-adrenoceptor agonists for the treatment of respiratory disorders is desirable since the most frequently encountered side effects of these agents include tachycardia, palpitations, tremors, anxiety, and metabolic abnormalities.
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