RECEPTOR INTERACTIONS OF IMIDAZOLINES .6. SIGNIFICANCE OF CARBON BRIDGE SEPARATING PHENYL AND IMIDAZOLINE RINGS OF TOLAZOLINE-LIKE ALPHA-ADRENERGIC IMIDAZOLINES

  • 1 January 1980
    • journal article
    • research article
    • Vol. 214  (3) , 535-540
Abstract
The pharmacological significance of the C bridge separating the imidazoline and phenyl rings of tolazoline-like .alpha.-adrenergic imidazolines was investigated. Extending the C bridge to 2 C atoms, or deleting the C bridge, lowers affinity of the imidazolines for the .alpha.-receptor [from rat thoracic aorta] and markedly decreases or abolishes efficacy (i.e., agonist activity), suggesting that a single C atom optimally separates the phenyl and imidazoline rings. Although 1 C is optimal for .alpha. adrenergic activity, this particular atom does not appear to be essential since N may substitute for C with no marked or consistent changes observed in affinity or efficacy. Hydroxylation of the C bridge decreases affinity for the receptor .apprx. 10-fold but does not alter efficacy, but a similar substitution made in the norepinephrine-series of phenethylamines markedly increases affinity. With both the imidazolines and phenethylamines, this C atom may stereoselectively influence binding to the receptor. The C atom bridging the phenyl and imidazoline rings of tolazoline-like imidazolines serves only to provide optimal separation between the rings and does not contribute directly to the binding process. It is proposed that .alpha.-adrenergic imidazolines interact differently with the .alpha.-adrenergic receptor than the norepinephrine-like phenethylamines.