Structure-activity relationship at alpha-adrenergic receptors within a series of imidazoline analogues of cirazoline

Several analogues of cirazoline (2), a selective alpha(1)-adrenoreceptor agonist, were prepared and their pharmacological profiles studied. Although at the alpha(1)-adrenoreceptor all the compounds displayed a significant agonist activity, at the alpha(2)-adrenoreceptor they showed either agonist or antagonist activity depending on the nature of the phenyl substituent. The qualitative structure-activity relationship led us to the conclusion that the oxygen atom in the side-chain is essential for alpha(1)-agonist activity, while the cyclopropyl ring is not, and may be replaced by several groups. Of the groups studied, isopropoxy appears to be the best. Instead, the same substitution (i.e., isopropoxy for the cyclopropyl ring) at alpha(2)-adrenoreceptors causes a reversal of activity. On the other hand, the cyclopropyl ring seems to be important for alpha(1)-selectivity. Compound 20 is the most potent alpha(1)-agonist of the series, being equiactive with cirazoline on rat vas deferens and in pithed rat. (C) 2000 Elsevier Science Ltd. All rights reserved.