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Several analogues of cirazoline (2Chart 1), a selective α1-adrenoreceptor agonist, were prepared and their pharmacological profiles studied. Although at the α1-adrenoreceptor all the compounds displayed a significant agonist activity, at the α2-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 α1-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 α2-adrenoreceptors causes a reversal of activity. On the other hand, the cyclopropyl ring seems to be important for α1-selectivity. Compound 20is the most potent α1-agonist of the series, being equiactive with cirazoline on rat vas deferens and in pithed rat.

A series of 2- trans -styryl-imidazoline ( tracizoline ) congeners were designed and tested to develop 2-D and 3-D QSAR models for their binding to imidazoline (I 2 ) receptor. The important role of lipophilicity was assessed by classical 2-D QSAR study (Hansch approach) and by comparative molecular field analysis (CoMFA) with the inclusion of the molecular lipophilicity potential (MLP), as an additional descriptor, besides standard steric and electrostatic fields. Results from these studies were compared to those obtained in a previous modeling study of I 2 receptor ligands and integrated into a new, comprehensive model, based on about sixty I 2 receptor ligands. This model revealed, at the three-dimensional level, the most significant steric, electrostatic, and lipophilic interactions accounting for high I 2 receptor affinity.