Pharmacological properties of the enantiomers of idazoxan: possible separation between their alpha-adrenoceptor blocking effects.

The alpha-adrenoceptor blocking properties of the two enantiomers of idazoxan have been investigated in rats, dogs and chicks, as well as their agonistic effects in pithed rats. At peripheral sites, (+) idazoxan was equipotent for blocking both postsynaptic alpha-1 and alpha-2 adrenoceptors of the rat and revealed to be a potent antagonist at presynaptic sites of rats and dogs. (-) Idazoxan revealed to be selective for postsynaptic alpha-2 adrenoceptors with an apparent selectivity ratio of about 10. This selectivity of (-) idazoxan was greater in vitro. (-) Idazoxan also antagonized presynaptic alpha-2 adrenoceptors of rats and dogs. At central sites, (+) and (-) idazoxan antagonized the hypotension, bradycardia, inhibition of sympathetic nerve activity induced by clonidine in rats and dogs and sedation induced by clonidine and azepexole in chicks. Although (+) idazoxan was more potent than (-) idazoxan, binding studies revealed (-) idazoxan to be more selective than (+) idazoxan at central sites. It is concluded that (+) idazoxan antagonizes both alpha-1 and alpha-2 adrenoceptors and (-) idazoxan is selective for alpha-2 adrenoceptors. In the pithed rat, only (-) idazoxan possesses both alpha-1 and alpha-2 agonistic effects. These results show little differences between the two enantiomers of idazoxan as for those of imidazoline derivatives.

Antagonistic effects of S9871 or (imidazolinyl-2)-2-dihydro 2,3 benzofurane and its stereoisomers on some central and peripheral actions of alpha 2-agonists.

(+/-) and (+), but not (-) S9871 are new alpha 2-adrenoceptor selective antagonists. The effect of the racemic mixture and of the stereoisomers on cardiovascular and sedative responses to clonidine have been studied in rats and chickens, respectively. Blockade of central alpha 2-adrenoceptors was also measured as a recovery of the sympathoinhibitory effect induced by intravenous administration of B-HT 933 (azepexole). The potency profiles of these agents established in the central nervous system were confirmed in studies using the vas deferens in situ in the pithed rat. (+/-) and (+) S9871 blocked and antagonized some centrally mediated effects of clonidine such as the depressor response to both intravenous and intracerebroventricular administration. However, the return of arterial pressure to the control value, after intravenous administration of (-) S9871, does not result from an antagonistic action on alpha 2-adrenoceptors, since the depressor effects of clonidine were not blocked, but could be explained by alpha-agonistic properties of (-) S9871. (+/-) and (+) S9871 also blocked and antagonized the hypotensive and bradycardic action induced by intravenous administration of B-HT 933. The loss of the righting reflex induced by clonidine in the chicken was prevented by (+/-) and (+) S9871, as shown by a shift of the dose-response curve to clonidine to the right by both agents; on the contrary, (-) S9871 potentiated the sedation induced by clonidine. In the pithed rat, intravenously administered (+/-) and (+) S9871 fully antagonized the inhibitory effects of clonidine on the electrically induced contractions of the vas deferens. These observations are consistent with a selective alpha 2-adrenoceptors antagonistic effect of (+/-) and (+) S9871 at central and peripheral alpha 2-adrenoceptors.

Stereoselectivity of central alpha-adrenoceptors involved in sleep induced by clonidine in chickens.

The stereoselectivity of central alpha 2-adrenoceptors involved in sleep induced in chicks by clonidine, suggested by the results observed with the stereoisomers of idazoxan, was further investigated with the stereoisomers of (imidazolinyl-2)-2-dihydro-2,3-benzofurane (S9871) and those of (imidazolinyl-2)-2-benzocyclobutane (S10089). As for the stereoisomers of idazoxan, there was not a good separation between the effects of the stereoisomers of S10089. In contrast, there was a clearcut separation between the effects of (+)S9871 (antagonist) and (-)S9871 (no effect against the action of clonidine). Therefore, these results strongly support the view that central alpha 2-adrenoceptors which mediate sedation are stereoselective for alpha 2-antagonists.

[In vivo and in vitro study of (N-piperidinomethyl)-2-chromanne on pre- and postsynaptic alpha-adrenoreceptors in the rat]. / Etude in vivo et in vitro du (N-pipéridinométhyl)-2-chromanne sur les alpha-adrénocepteurs pré- et postsynaptiques du rat.

The alpha-adrenoceptors blocking effect of (N-piperidinomethyl)-2-chromanne was studied in vivo and in vitro in the rat. In the pithed rat, (N-piperidinomethyl)-2-chromanne (1 mg/kg i.v.) antagonized the pressor effects induced by alpha agonists. (N-piperidinomethyl)-2-chromanne competitively antagonized the pressor effects of M7 (alpha 2-agonist) and cirazoline (alpha 1-agonist). (N-piperidinomethyl)-2-chromanne antagonized the inhibitory effects of clonidine on presynaptic alpha 2-receptors in stimulated pithed rats. On the vas deferens of the rat (N-piperidinomethyl)-2-chromanne antagonized the inhibitory effects of clonidine on the twitch response produced by electrical stimulation and also the contractions induced by phenylephrine. This derivate appears to be an alpha 1 and alpha 2 blocking agent.

(Imidazolinyl-2)-2-benzodioxane 1-4 (idazoxan) and its stereoisomers, new alpha 2-antagonists.

Since (+/-) idazoxan is well known as alpha 2-antagonist, the present report described some results on the alpha-adrenoceptor blocking properties of the stereoisomers of idazoxan. At peripheral sites, (+) idazoxan revealed to be equipotent for blocking postsynaptic alpha 1- and alpha 2-adrenoceptors of the rat. On the other hand, it revealed to be a full antagonist of the inhibitory effects of clonidine on presynaptic alpha 2-adrenoceptors of rats. However, in vitro investigations have shown (+) idazoxan to be less selective than (-) idazoxan for alpha 2-adrenoceptors. (-) Idazoxan was selective for postsynaptic alpha 2-adrenoceptors and antagonized presynaptic alpha 2-adrenoceptors of the rat. Results obtained in central investigations revealed species differences between chickens and mice. The present results led to the conclusion that (+) idazoxan was equipotent on alpha 1- and alpha 2-adrenoceptors whereas (-) idazoxan was selective for alpha 2-adrenoceptors. On the other hand, they suggested a stereoselectivity of peripheral and central alpha 2-adrenoceptors for alpha-antagonists.

[Partial agonist properties of a new derivative of dihydrobenzofuran, S 9871, and its stereoisomers in pithed rats]. / Etude des propriétés agonistes partielles d'un nouveau dérivé du dihydrobenzofurane, le S 9871, et de ses stéréoisomères chez le rat amyélé.

In the pithed rat, (imidazolinyl-2)-2 dihydro 2,3 benzofuran or S 9871 and its stereoisomers were found to block alpha-adrenoceptors. In the present investigation the agonistic effect were studied in pithed rats. With (+/-) and (+) S 9871 this effect is compatible with a stimulation of alpha 1-adrenoceptors and the effect of (-) stereoisomer with a stimulation of alpha 1 and alpha 2 adrenoceptors.

Pre- and postsynaptic alpha-adrenoceptor blocking properties of a new dihydrobenzofurane derivative (imidazolinyl-2)-2-dihydro 2,3 benzofurane (S 9871) and its stereoisomers in rats.

In the present investigation, the alpha-adrenoceptor blocking effect of (imidazolinyl-2)-2-dihydro 2,3 benzofurane or S 9871 and its stereoisomers was studied. In the pithed rat (+/-) and (+) S 9871 competitively antagonized the pressor effects of azepexole and clonidine more effectively than those of cirazoline and phenylephrine. (-) S 9871 only blocked the pressor response of the alpha 1-agonists used: phenylephrine and cirazoline. (+/-) and (+) S 9871 antagonized the inhibitory effects of clonidine on the increase in heart rate produced by stimulation of the sympathetic efferent fibres of the thoracic spinal cord. (-) S 9871 was twenty times less potent on the decrease in heart rate induced by clonidine. On the vas deferens of the rat, (+/-) and (+) S 9871 appeared to be more potent than (-) S 9871 in antagonizing the inhibitory effects of clonidine on the twitch response produced by electrical stimulation. Therefore, (+/-) and (+) S 9871 appear to be more preferential for alpha 2-adrenoceptors than for alpha 1-adrenoceptors; in contrast (-) S 9871 appears to be selective for alpha 1-adrenoceptors. (+/-) and (+) S 9871 appears to be one of the most selective agents for blocking alpha 2-adrenoceptors.

[Effect of 2 new derivatives of imidazoline and their optical isomers on postsynaptic alpha adrenergic receptors in pithed rats]. / Action de deux nouveaux dérivés de l'imidazoline et de leurs isomères optiques sur les récepteurs adrénergiques alpha postsynaptiques du rat amyélé.

The effects of the stereoisomers of two alpha adrenoceptor antagonists [S 10089 (Imidazolinyl-2)-2 benzocyclobutane and S 9871 (Imidazolinyl-2)-2 dihydro 2,3 benzofuran] were studied in pithed Rats. Vasoconstriction elicited via stimulation of alpha 1 adrenoceptors by cirazoline was antagonized, stimulation of alpha 2 adrenoceptors by azepexole was also antagonized by all these derivatives except (-) S 9871 which was ineffective on the pressor response of azepexole.

[Nature of alpha receptors implicated in the hypertensive effect of high doses of isoprenaline in dogs and rats]. / Nature des récepteurs alpha impliqués dans l'action hypertensive des fortes doses d'isoprénaline chez le chien et le rat.

Isoproterenol injected intravenously in dogs (3 mg/kg-1) and rats (5 mg/kg-1) induced an increase in blood pressure. After alpha 1 blockade (by AR-C 239, 0.1 mg . kg-1 i.v.) or alpha 2 blockade (by yohimbine, 1 mg/kg-1 i.v.) isoproterenol, as adrenaline, again induced an increase in blood pressure. This hypertensive effect was suppressed by an alpha 2 adrenoceptor blocking agent after an alpha 1 adrenoceptor blocking agent, and vice versa. These results are compatible with stimulation by high doses of isoproterenol of both alpha 1 and alpha 2 adrenoceptors to produce increase in blood pressure.

Peripheral postsynaptic alpha-adrenoceptor blocking properties of some new dihydrobenzofurane and imidazoline derivatives in pithed rats.

Peripheral postsynaptic alpha-adrenoceptor blocking properties of six new dihydrobenzofurane and imidazoline derivatives have been investigated in pithed rat against the pressor effects of phenylephrine and cirazoline (alpha 1-agonists) and clonidine and azepexole (alpha 2-agonists). Except for (N-methylimidazolinyl-2)-2 dihydro-2,3 benzofurane (II) that acted neither on alpha 1- nor alpha 2-adrenoceptors, all the compounds revealed blocking effects - plus or minor - on both alpha 1- and alpha 2-adrenoceptors. (Imidazolinyl-2)-2-chloro-7 dihydro-2,3-benzofurane (IV) is equipotent in blocking both alpha 1- and alpha 2-adrenoceptors. 7-Methoxy-(imidazolinyl-2)-2 dihydro-2,3-benzofurane (III) and (imidazolinyl-2)-2-fluoro-7-dihydro-2,3-benzofurane (V) block more effectively alpha 1- than alpha 2-adrenoceptors whereas (imidazolinyl-2)-2-benzocyclobutane (VI) is more potent in blocking alpha 2- than alpha 1-adrenoceptors. (Imidazolinyl-2)-2-dihydro-2,3-benzofurane (I) is a preferential alpha 2-adrenoceptor blocking agent. The most effective agents on alpha 2-adrenoceptors are under further pharmacological investigations.

[Interactions between alpha 1, alpha 2 and beta receptors in the blood pressure effects of adrenaline and noradrenaline in the dog]. / Interactions entre les récepteurs alpha 1, alpha 2 et beta dans les effets tensionnels de l'adrénaline et de la noradrénaline chez le chien.

In anaesthetized dog, the adrenaline induced hypertension is reversed by both alpha 1- and alpha 2-adrenoceptor blocking agents such as AR-C 239 and yohimbine. After alpha 1 or alpha 2 and beta-blockade, adrenaline induced again an increase in blood pressure. This hypertensive effect was suppressed by an alpha 2-adrenoceptor blocking agent when an alpha 1-adrenoceptor blocking was responsible for the reversal of adrenaline-induced hypertension, and conversely. After beta-blockade, both alpha 1- and alpha 2-adrenoceptor blockade is necessary for suppressing any tensional effect of adrenaline. On the other hand, alpha 1- and alpha 2-adrenoceptor blockade are both required to prevent beta-blockade from restoring adrenaline hypertensive effect. Similar effects were observed wih noradrenaline. In fact, only a significant decrease of the noradrenaline-induced hypertension was observed after each alpha-blocker. Both alpha 1- and alpha 2-adrenoceptor blocking agent also significantly inhibited the hypertension induced by noradrenaline. For completely suppressing the effect of noradrenaline on blood pressure, a combination of alpha 1, alpha 2 and beta-blockade is necessary. These results are compatible with a stimulation by adrenaline and noradrenaline of both alpha 1- and alpha 2-adrenoceptors to produce increase in blood pressure.

Action of stereoisomers of (imidazolinyl-2)-2-benzodioxane-1-4 or 2-(2-(1,4-benzodioxanyl))-2-imidazoline (170 150; RX 781094) on peripheral presynaptic and central alpha 2-adrenoceptors.

In the vas deferens of the rat, (-)-170 150 (imidazolinyl-2)-benzodioxane-1-4 or 2-(2-(1,4-benzodioxanyl))-2-imidazoline appeared to be more selective than (+)-170 150 for antagonizing the inhibitory effects of clonidine on the twitch response. In contrast, (+)-170 150 was the most potent of the two isomers for antagonizing the centrally mediated clonidine- or azepexole-induced sleep in chickens. These unexpected results seem to indicate that there are several subpopulations of alpha 2-adrenoceptors.

In vitro studies with (imidazolinyl-2)-2-benzodioxane-1-4 ((+/-)-170 150), a new potent alpha 2-adrenoceptor blocking agent.

In rat vas deferens, (+/-)-170 150 proved to be an alpha 2-adrenoceptor blocking agent with a high alpha 2/alpha 1 selectivity ratio. In rat cerebrocortical membranes, (+/-)-170 150 was seven times more potent than yohimbine for inhibiting specific [3H]clonidine binding. However, (+/-)-170 150 appeared to be 3.5 times less selective for alpha 2-adrenoceptors sites than yohimbine. These results indicate that (+/-)-170 150 is a potent preferential alpha 2-adrenoceptor blocking agent, as had been shown by in vivo experiments.

[Comparative study of piperoxan and 2-(2-imidazolinyl)-1, 4-benzodioxane (170 150) on pre- and postsynaptic receptors in the rat]. / Etude comparative du pipeéroxane et de l'(imidazolinyl-2)-2-benzodioxane 1-4 (170 150) sur les récepteurs pré- et postsynaptiques du rat.

1. 170 150 (imidazolinyl-2)-2-benzodioxane 1-4), as does piperoxan, competitively antagonizes the hypertension induced by clonidine in the pithed rat. Piperoxan appears slightly less potent than 170 150 in this preparation as shown by the comparison of the apparent pA10 values: 5.3 for piperoxan versus 5.4 for 170 150. 2. The two drugs antagonize the reduction of the electrically-induced tachycardia produced by clonidine. 170 150 appears to be 3-fold more potent than piperoxan in this preparation. 3. These results are compatible with a blockade of alpha 2-pre and postsynaptic adrenoceptors of the rat by piperoxan and 170 150 appears to be 3-fold more potent than piperoxan in this preparation. 3. These results are compatible with a blockade of alpha 2-pre and postsynaptic adrenoceptors of the rat by piperoxan and 170 150 and they are in agreement with our previous results which indicate that compound 170 150 shows a preferential affinity for alpha 2-adrenoceptors.

Interaction between mianserin and clonidine at alpha 2-adrenoceptors.

The purpose of the present study was to characterize the effects of mianserin at alpha 2-adrenoceptors. Firstly, the action of mianserin on postganglionic sympathetic fibres has been studied using the tachycardia induced by stimulation of the cardiac nerve in dogs. Mianserin increased this tachycardia, but could not prevent the inhibitory effect of clonidine in this model. However, an antagonistic effect of mianserin against clonidine was observed when animals were pretreated with desipramine. Secondly, mianserin antagonized the inhibitory effect of clonidine on the electrically stimulated guinea-pig ileum. In high concentrations, mianserin reduced both electrically and acetylcholine induced contractions. Thirdly, mianserin antagonised the sleep induced by clonidine in chickens. These results are consistent with alpha 2-adrenoceptor blocking properties of mianserin in peripheral noradrenergic fibres in dogs, in cholinergic fibres in guinea-pig ileum and in the central nervous system in chickens.

Pre- and postsynaptic a-adrenoceptor blockade by (imidazolinyl-2)-2-benzodioxane 1-4 (170 150): antagonistic action on the central effects of clonidine.

While the specificities of alpha 1-adrenoceptor blocking agents are considered as satisfactory, those of alpha 2-adrenoceptor blocking agents are only weak. Therefore, a more selective alpha 2-adrenoceptor blocking agent is needed. In anaesthetized dogs and rats, (imidazolinyl-2)-2-benzodioxane 1-4 (170 150), a benzodioxane derivative, antagonized the pressor effects induced by adrenaline, noradrenaline and phenylephrine, but did not modify the effects of acetylcholine, histamine and isoprenaline. Therefore, its selectivity is satisfactory. In the anaesthetized dog, 170 150 (0.1 mg.kg-1) increased the tachycardia induced by electrical stimulation of the cardiac sympathetic nerve and antagonized the inhibitory effects of clonidine. In addition, 170 150 blocked and reversed some centrally mediated effects of clonidine such as the fall in blood pressure, bradycardia and reduction of splanchnic discharges in the dog, and the loss of the righting reflex induced by clonidine in the chicken. The centrally mediated effects of clonidine are attributed to stimulation of alpha 2-adrenoceptors; therefore, 170 150 appears to antagonize these alpha-adrenoceptors. Moreover, 170 150 appears to be more potent than piperoxan.

Effects of nicergoline on the cardiovascular system of dogs and rats.

In pentobarbitalized closed-chest dogs, nicergoline (10--100 microgram/kg, i.v.) reduced blood pressure, heart rate, and splanchnic nerve activity. Intracisternal administration of nicergoline (3 microgram/kg) only reduced splanchnic nerve activity. In open-chest dogs, nicergoline reduced blood pressure, cardiac output, and total peripheral resistance but did not change heart rate. In pithed rats treated with a beta-adrenoceptor-blocking agent, nicergoline reduced the pressor responses to noradrenaline and adrenaline. Nicergoline slightly attenuated the pressor responses of dogs to noradrenaline and tyramine and, in addition, reversed the hypertension induced by adrenaline and dimethylphenylpiperazinium. Nicergoline (100 microgram/kg) increased the tachycardia induced in dogs by stimulation of the right cardiovascular nerve and prevented the inhibitory effect of clonidine on this response. However, nicergoline only partially antagonized the effect of clonidine once it was fully established. Nicergoline did not antagonize the hypotensive and bradycardic effects of clonidine when they were established. Nicergoline did not affect the vagally mediated bradycardia evoked by carotid nerve stimulation in beta-adrenoceptor-blocked dogs. The compound did not change blood pressure in Cl spinal cord transected dogs. In conclusion, nicergoline appears to decrease blood pressure by blocking alpha-adrenoceptors and, at least at some doses, by a central inhibition of the sympathetic tone. Nicergoline appears to be a preferential alpha 1-adrenoceptor-blocking agent.

Effects of some alpha-adrenoceptor agonists and antagonists on the guinea-pig ileum.

The purpose of the present study was to further characterize the alpha-adrenoceptors located on parasympathetic fibres. Segments of guinea-pig ileum were stimulated by transmural electrical pulses, and the ensuing contractions, which are due to the release of acetylcholine from postganglionic parasympathetic fibres, were monitored. Clonidine and tramazoline, which are thought to act preferentially on presynaptic alpha-adrenoceptors, reduced the contractions, whereas phenylephrine and methoxamine, postsynaptic alpha-adrenoceptor agonists, were ineffective. Contractions induced by acetylcholine were not changed by clonidine but were abolished by atropine. Yohimbine, piperoxan, phentolamine and the thymoxamine reversed or prevented the inhibitory effect of clonidine. Prazosin and AR-C239 did not antagonize this effect. The inhibitory effect of tramazoline was antagonized by piperoxan but not AR-C239 or by prazosin. Naloxone did not alter the action of clonidine, and piperoxan did not change the inhibitory effect of morphine. In conclusion, these experiments suggest the presence on cholinergic postganglionic fibres of both opiate receptors and alpha-adrenoceptors.. The latter appear to resemble more closely alpha 2-adrenoceptors than alpha 1-adrenoceptors.

[Pharmacologic study of several alpha-adrenolytics]. / Etude pharmacologique de quelques dérivés alpha-adrénolytiques.

Six alpha-adrenoceptor blocking agents have been investigated in dogs and rats. 170 150 and 170 153 have been found the most potent of these agents. At low doses (0,1 microgram/kg) they reversed the pressor response to low doses of adrenaline (0,1 and 0,3 microgram/kg) and suppressed the response to high doses of adrenaline. They reduced the pressor response to noradrenaline. In addition, in dogs 170 150 increased the tachycardia caused by stimulation of the cardiac nerve. The compound prevented and reversed the inhibition caused by clonidine on the effects of cardiac nerve stimulation. 170 153 did not increase the tachycardia caused by cardiac nerve stimulation, but it prevented and reversed the inhibitory effects of clonidine on this stimulation. The results show that 170 150 and 170 153 are potent alpha-adrenoceptor blocking agents acting on both pre and post-synaptic alpha-adrenoceptors which could be interesting pharmacological tools.