α1-Adrenoceptor activation: A comparison of 4-(Anilinomethyl)imidazoles and 4-(Phenoxymethyl)imidazoles to related 2-imidazolines

Literature reports suggest that disruption of an interhelical salt bridge is critical for α1-adrenoceptor activation, and the basic amine found in adrenergic receptor ligands is responsible for the disruption. Novel 4-(anilinomethyl)imidazoles and 4-(phenoxymethyl)imidazoles are agonists of the cloned human α1-adrenoceptors in vitro, and potent, selective α1A-adrenoceptor agonists have been identified in this series. These imidazoles demonstrate similar potencies and α1-subtype selectivities as the corresponding 2-substituted imidazolines. The extremely close SAR suggests that, in spite of the large difference in basicity, these imidazoles and imidazolines may establish the same interactions to activate α1-adrenoceptors.