Receptor Interactions of Imidazolines (1982)

Clonidine and its methylene-bridged analog, St 1913, were potent α1 and α2 adrenergic agonists in vitro. The activity of each compound at each α-receptor subtype was similar indicating that changing the nitrogen bridge of clonidine to a methylene bridge (as in St 1913) does not markedly alter the pharmacology of the compound at the receptor level. This was confirmed in vivo by the fact that the pressor effects of both compounds in pithed rats, and the depressor effects in spontaneously hypertensive rats after intracisternal administration, were also similar. The α2/α1 selectivities of the compounds as assessed in vitro (ileum/aorta) and in vivo (pithed rat) were also similar to each other indicating that α-receptor subtype specificity is not greatly affected by changing the nitrogen bridge to a methylene bridge. Although no major differences were noted at the receptor level, significant changes in the physicochemical properties of the molecule were observed when the nitrogen bridge was changed to a methylene bridge. The pKa of clonidine was found to be 7.7 and that of St 1913 was 9.7. This corresponds to a large difference in the percent of each compound existing in the un-ionized species at physiological pH. Although both compounds exist predominantly in the ionized form at pH 7.4 (i.e., 67% for clonidine and 99.5% for St 1913), the percent existing in the un-ionized form is approximately 66 times greater for clonidine (33%) than for St 1913 (approximately 0.5%). While these differences in ionization (or un-ionization) did not influence drug effects at the receptor level, they did influence the overall pharmacology of the two compounds, and may account for large differences in antihypertensive potency between clonidine and St 1913. As a result, clonidine, which has similar activity as St 1913 at the receptor level, is approximately 25-fold more potent than St 1913 as an antihypertensive after intravenous administration to spontaneously hypertensive rats. Since both compounds possess equal abilities to lower blood pressure when administered beyond the blood-brain barrier (intracisternal administration), these results following intravenous administration indicate that clonidine penetrates the blood-brain barrier at a far greater rate than St 1913, and thereby more readily gains access to the site of action within the central nervous system. This, in turn, results from the greater percentage of clonidine existing in the un-ionized form relative to St 1913, and it is this un-ionized form which would more readily penetrate the blood-brain barrier. Likewise, the ability of these compounds to exit the brain via diffusion in the opposite direction through the blood-brain barrier is also influenced by the extent of ionization at physiological pH. Thus, clonidine, by virtue of existing in the un-ionized form to a greater extent than St 1913, will diffuse from the central nervous system into the periphery at a greater rate than St 1913. The results also indicate that while the un-ionized species more readily penetrates the blood-brain barrier, it is the ionized form which appears to bind to, and subsequently activate, the receptor.