The main hypothesis under consideration is to establish whether the proposed modifications of trimetoquinol (TMQ) will produce agents which are highly potent and selective for subtypes of beta- adrenergic and thromboxane A2 (TXA2) receptor systems. Our studies will emphasize evaluation of newly synthesized TMQ analogs on pharmacological receptors in lung (beta 2), cardiovascular (beta 1), platelets (TXA2, aggregation, alpha) and smooth muscle, (TXA2, tone, tau) systems. Using stereoisomers and analogs of TMQ, we plan to search for compounds which interact selectively with different subtypes of beta2-adrenergic (skeletal muscle versus tracheal muscle) and thromboxane A2 (platelet versus vascular smooth muscle) receptors. Based on our previous work we have divided our synthetic objectives with TMQ analogs into three areas: 1) Synthesis of reversible agonists and antagonists including (a) optical isomers of fluorinated TMQ analogs that have shown selective beta 2 agonist and TXA2 antagonist properties, (b) analogs of TMQ that should have lowered phenolic pKa values and higher beta 2/beta 1-selectivity, and (c) cyclopropane analogs of TMQ for gaining insight into conformational requirements for beta 2-agonist and TXA2 antagonist activities; 2) Synthesis of optically active radioligands for characterizing subtypes of TXA2 and beta-adrenergic receptor binding sites; and 3) Synthesis of affinity and photoaffinity labels that should allow us to probe various binding sites on beta- adrenergic and TXA2 receptors. These compounds will be tested for their 1) potency as agonists or antagonist in tracheal, atrial, and skeletal muscle preparations; and 2) potency and specificity as antagonists of TXA2 mediated platelet aggregation and vascular smooth muscle contraction. Development of highly selective beta 2-adrenergic agonists for the treatment of respiratory disorders is desirable since the most frequently encountered side effects of these agents include tachycardia, tremors, and metabolic abnormalities. In recent years, a significant separation of undesirable cardiac stimulation from beneficial bronchodilation has been accomplished; however, to date, no separation of beta 2-adrenergic effects on skeletal muscle (tremor) from bronchodilation has been observed. The use of TXA2 receptor antagonists as probes will aid in the delineation of the biological role of this mediator in humans; and such agents should be useful in the treatment of vascular and thrombotic disorders commonly associated with coronary heart diseases.
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