Receptor Interactions of Imidazolines

Abstract

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 ...

Adrenoceptor blocking properties of atropine‐like agents anisodamine and anisodine on brain and cardiovascular tissues of rats

“…The K, values for the displacement of [3HJ-WB-4101 binding by atropine and scopolamine determined in the present study are in close agreement with values obtained by others (Cantor et al, 1983). Although rat aorta does contain both a,-and a2-adrenoceptors (Ruffolo et al, 1982), the effects of phenylephrine are almost entirely due to a stimulation of ax1-adrenoceptors (Digges & Summers, 1983). Likewise, phenylephrine has been used as the agonist of choice for a study of a1-adrenoceptormediated effects on the left atria of rats (Benfey et al, 1979).…”

“…We used established techniques for a quantitation of the interaction between atropine-like agents and aadrenoceptor radioligands (Abraham et al, 1981;Cantor et al, 1983) and for estimating the antagonism against phenylephrine on isolated rat aortic strips (Ruffolo et al, 1982;Digges & Summers, 1983) and left atria (Benfey et al, 1979). The K, values for the displacement of [3HJ-WB-4101 binding by atropine and scopolamine determined in the present study are in close agreement with values obtained by others (Cantor et al, 1983).…”

Presynaptic α‐adrenoceptors: do exogenous and neuronally released noradrenaline act at different sites?

“…However, yohimbine did not antagonize the effects of noradrenaline either. It might be argued that the concentration of yohimbine (1 x 10-7M) was too low to exert any appreciable antagonism of noradrenaline, yet it is generally found that the threshold blocking concentration of yohimbine at presynaptic a2-adrenoceptors is 1 x 10-8 -3 x 10-8M (Ruffolo et al, 1981) and, anyway, the concentration of yohimbine used in the present experiments (1 x 10-7M) was enough to increase markedly the stimulation-evoked overflow of radioactivity. Perhaps the yohimbine-induced increase in stimulation-evoked overflow was responsible for the apparent failure of yohimbine to antagonize the effects of exogenous noradrenaline.…”

The determination of presynaptic pA2 values of yohimbine and phentolamine on the perfused rat heart under conditions of negligible autoinhibition

“…These constants, derived from postsynaptic responses to cholinergic nerve stimulation, closely agree with our pA2 value of 7.82 obtained by measuring the [3H]-noradrenaline overflow. The pA2 values of yohimbine at postsynaptic receptor sites in aortae of species other than rat are 6.6 (guinea-pig, Grundstrom etal., 1981), 6.7 (rabbit, Furchgott, 1955) and 6.8-6.9 (cat, dog and hamster, Ruffolo, Waddell & Yaden 1982). Thus, the affinity of yohimbine for presynaptic receptors appears to be at least one log unit higher than for the classical postsynaptic oa-adrenoceptors.…”