Hypotensive properties of benzodioxane derivatives structurally related to R 28935. Comparison of activity with some receptor affinities.

Hypotensive activities were determined of some derivatives of erythro 1-(1-[2-(1,4-benzodioxane-2-yl)-2-hydroxyethyl]-4-piperidyl)-2-benzimidazolinone (R 28935) following intravenous administration to anaesthetized normotensive rats. Introduction of chlorine into the benzimidazolinone part of R 28935 negatively influenced the hypotensive potency as did opening of the dioxane ring. An appropriate substituent restored the hypotensive effectiveness of the "opened" structures. In general, the compounds were weak inhibitors of the specific binding of (3H)-prazosin (alpha 1-adrenoceptors), (3H)-clonidine (alpha 2-adrenoceptors) and (3H)-dihydromorphine (opiate-receptors) to rat brain membranes. The relative order of affinity for either receptor did not correspond with that of the hypotensive activity. Previous (-15 min) intravenous treatment with phentolamine (0.2 mg/kg) abolished the depressor effect of prazosin and diminished that of the threo form R 29814 as well as of all "opened" congeners, but did not significantly reduce the hypotensive response to R 28935 and the other erythro structures. It is concluded that neither alpha 1- and alpha 2- nor opiate-receptors are involved as the primary targets for R 28935 and its congeneric drugs to induce hypotension. The exact mechanism of action remains therefore unsolved. Erythro R 28935 and the other racemic erythro mixtures are centrally acting hypotensive agents. A peripheral alpha-sympatholytic component may contribute to the overall depressor effect of threo R 29814 and the "opened" derivatives.

Inhibition of R 28935- and R 29814-induced hypotension by prazosin in anaesthetized normotensive rats.

The intravenous administration of erythro 1-(1-[2-(1,4-benzodioxane-2-yl)-2-hydroxyethyl]-4-piperidyl)-2-benzimidazolinone R 28935) and the threo from R 29814 to anaesthetized normotensive rats showed a dose-dependent decrease in mean arterial pressure. Previous (-1 hr) intraperitoneal (0.1 mg/kg) as well as subcutaneous (0.03 mg/kg) treatment with the alpha 1-adrenoceptor blocking drug prazosin antagonized the hypotensive responses to R 28935 and R 29814. The selective antagonist of alpha 2-adrenoceptors yohimbine (0.5 mg/kg) was ineffective. On the other hand, the hypotensive action of clonidine was hardly affected by this prazosin treatment, whereas yohimbine now significantly impaired it. R 28935 and R 29814 showed no direct alpha-adrenoceptor stimulating properties and were moderately active in inhibiting the pressor response to (-)-phenylephrine in pithed normotensive rats when compared with phentolamine and prazosin. The results confirm and extend previous findings in cats. It is concluded that in some way central alpha 1-adrenoceptors are involved in the hypotensive mechanism of R 28935 (R 28914). However, central alpha 1-adrenoceptors are probably not the common sites of interaction, since any alpha 1-adrenoceptor-stimulating potency is lacking for R 28935 (R 29814) and their (moderate) affinity for alpha 1-adrenoceptors bears no relationship to their hypotensive activity.

Discrimination between peripheral and central alpha-adrenergic effects using meta-substituted imidazolidines.

meta-Substituted 2-chlorophenyl(imino)imidazolidines of the clonidine-type (2,3- and 2,5-substituted derivatives) were used in attempts to discriminate between alpha-adrenergic effects (central hypotensive and peripheral hypertensive activities) in rats. The central hypotensive activity of four pairs of substitution isomers was expressed as a pC20, calculated from log dose-response curves after i.v. administration of the compounds to anaesthetized, normotensive rats. Peripheral hypertensive potency was evaluated in pithed normotensive rats following i.v. injections and quantified by means of pC60. The partition coefficients of the drugs were determined in an octanol/aqueous buffer (pH 7.4, 37 degrees C) system as a measure of lipophilic behaviour. The pressor activities in rats were comparable within each pair of substitution isomers whereas the depressor potencies differed greatly, although the representatives within each pair displayed similar lipophilicity. Regression analysis showed that the central hypotensive activity was governed by the steric bulk of the 5-substituent. On the other hand, this feature did not affect the peripheral hypertensive potency. The discrepancy between central and peripheral alpha-adrenergic activities found for 2,5-substituted imidazolidines is discussed in connection with the selectivity of these compounds for alpha 1 and alpha 2-adrenoceptors.

Characterization of alpha-adrenoceptor populations. Quantitative relationships between cardiovascular effects initiated at central and peripheral alpha-adrenoceptors.

The agonist selectivities of central (medullary) and peripheral (vascular) alpha-adrenoceptors were compared in order to investigate a possible similarity among these two alpha-adrenoceptor populations. Linear regression equations were derived between the alpha-adrenergic potencies, mediated by these two types of alpha-adrenoceptors for 21 structurally dissimilar alpha-adrenoceptor agonists. Hypotensive potency after intravenous administration to anesthetized, normotensive rats was determined as a measure of central alpha-adrenergic activity and expressed as pC25, obtained from log dose-response curves. Peripheral alpha-adrenergic potency was quantified by means of the hypertensive effect elicited in pithed, normotensive rats after intravenous injections, yielding pC60 as the biological variable. A most significant linear relationship was generated between central hypotensive activity (pC25) and peripheral hypertensive potency (pC60), provided that log P' (octanol/buffer; pH 7.4, 37 degrees C) was included into the regression in a parabolic form. This result indicates that the central (medullary) alpha-adrenoceptors and the peripheral (vascular) alpha-adrenoceptor sites, which are excited by the drugs in question, make identical demands upon their agonists. The difference in accessibility to these peripheral and central alpha-adrenoceptor populations is adequately accounted for by a parabolic description in log P'. The apparent contradiction of this finding with the suggestion that central, hypotensive alpha-adrenoceptors are of the alpha 2 type and peripheral, vascular alpha-adrenoceptors belong to the alpha 1 subpopulation is discussed. The recent identification of an additional subclass of postsynaptic, vascular alpha 2-adrenoceptors and the lack of pronounced differential stimulating activity of the agonists at peripheral alpha-adrenoceptors may explain the present findings and clarify the paradox.