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Chiarino et al. [43] described some potent and remarkably selective b2-adrenoceptor agonists in a series of 1-(3-substituted-5-isoxazolyi)-2-alkyl-aminoethanol derivatives in which the isoxazole ring replaces the catechol moiety in the b-adrenergic compounds. From this series, the compound broxaterol (1) displayed a marked selectivity toward b2-receptors of the trachea and was selected for further development as a potential bronchodilatory agent.

It is important to point out that a selective response in vivo does not always reflect selectivity at the receptor level but may depend on organ selectivity. This is particularly true for partial agonists of low intrinsic efficacy, which may exhibit receptor-selective activity in a tissue containing a large receptor pool or may operate the receptor-effector coupling system more efficiently.

b2-Receptor agonists such as soterenol (2), fenoterol (3), and salbutamol (4) bind with approximately equal affinity to both b1- and b2-receptors but apparently owe their selectivity to greater efficacy at the latter receptor [44], whereas other agonists, such as procaterol (5), show greater affinity for b2-receptors [45]. In fact, procaterol is one of the most selective b2-adrenoceptor drugs known today.

There still appears to be a need to further improve the design of b2-receptor stimulant drugs. Factors such as receptor selectivity, metabolic stability, and structural manipulation to prolong action are actively being investigated. Whether selectivity can ever be achieved is questionable, because skeletal muscle tremor in humans is b2-receptor mediated [46], and the tachycardia exhibited by bronchodilator drugs appears to be mediated directly and indirectly through b2-receptors [47]. When given by the inhalation route, the absorption characteristics of b2-adrenoceptor stimulant drugs may well determine their duration of action; thus, a better understanding of the factors governing drug clearance from the respiratory tract after inhalation delivery is needed.

Another area for improvement is in the relative efficacy of b2-bronchodilators. Compounds with low efficacy may be effective at low levels of bronchoconstriction. But as the severity of bronchoconstriction increases, such compounds will become partial agonists before those of greater efficacy. Therefore, the relative efficacies of new compounds should be considered in drug development decisions.

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