Receptor interactions of imidazolines. IV. Structural requirements for alpha adrenergic receptor occupation and receptor activation by clonidine and a series of structural analogs in rat aorta.

Clonidine and a series of nine halogen and alkyl-substituted structural analogs were evaluated for alpha adrenergic receptor agonist activity in rat aorta. Phenylephrine was included for comparison. All the imidazolines were partial agonists with respect to phenylephrine due to the fact that they only weakly activated the receptor. Whereas phenylephrine requires approximately 0.2% receptor occupancy to produce a response 20% of maximum, the imidazolines required from 25 to 100% receptor occupancy to produce the same response. Although clonidine and its structural analogs are from 125 to 500 times weaker activators of the alpha adrenergic receptor than phenylephrine, they have from 2 to 60 times higher affinity for the receptor than phenylephrine. The results support our previous conclusions that a dichotomy exists between the factors that direct receptor occupation and receptor activation since the structural requirements for each of these parameters differ.