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 ag onist, were prepared and their pharmacological profiles studied. Although a t the alpha(1)-adrenoreceptor all the compounds displayed a significant ago nist 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 activit y, 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 sa me substitution (i.e., isopropoxy for the cyclopropyl ring) at alpha(2)-adr enoreceptors causes a reversal of activity. On the other hand, the cyclopro pyl ring seems to be important for alpha(1)-selectivity. Compound 20 is the most potent alpha(1)-agonist of the series, being equiactive with cirazoli ne on rat vas deferens and in pithed rat. (C) 2000 Elsevier Science Ltd. Al l rights reserved.