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In the present study we evaluated the alpha 1- and alpha 2-adrenoceptor subtype binding, central alpha 2-adrenoceptor antagonist potency, as well as effects on brain neurochemistry and behavioural pharmacology of two alpha 2-adrenoceptor antagonists, atipamezole and yohimbine. Atipamezole had higher selectivity for alpha 2- vs. alpha 1-adrenoceptors than yohimbine regardless of the subtypes studied. Both compounds had comparable affinity for the alpha 2A-, alpha 2C- and alpha 2B-adrenoceptors, but yohimbine had significantly lower affinity for the alpha 2D-subtype. This may account for the fact that significantly higher doses of yohimbine than atipamezole were needed for reversal of alpha 2-agonist (medetomidine)-induced effects in rats (mydriasis) and mice (sedation and hypothermia). The effect on central monoaminergic activity was estimated by measuring the concentrations of transmitters and their main metabolites in whole brain homogenate. At equally effective alpha 2-antagonising doses in the rat mydriasis model, both drugs stimulated central noradrenaline turnover (as reflected by increase in metabolite levels) to the same extent. Atipamezole increased dopaminergic activity only slightly, whereas yohimbine elevated central dopamine but decreased central 5-hydroxytryptamine turnover rates. In behavioural tests, atipamezole (0.1-10 mg/kg) did not affect motor activity but stimulated food rewarded operant (FR-10) responding (0.03-3 mg/kg) whereas yohimbine both stimulated (1 mg/kg) and decreased (or = 3 mg/kg) behaviour in a narrow dose range in these tests. In the staircase test, both antagonists increased neophobia, but in the two compartment test only yohimbine (or = 3 mg/kg) decreased exploratory behaviour. The dissimilar effects of the antagonists on neurochemistry and behaviour are thought to be caused by non alpha 2-adrenoceptor properties of yohimbine. In conclusion, the alpha 2-antagonist atipamezole blocked all alpha 2-adrenoceptor subtypes at low doses, stimulated central noradrenergic activity and had only slight effects on behaviour under familiar conditions, but increased neophobia. The low affinity for the alpha 2D-adrenoceptor combined with its unspecific effects complicates the use of yohimbine as pharmacological tool to study alpha 2-adrenoceptor physiology and pharmacology.

To investigate the effects of hydroxyl and methyl substitution of the alkyl bridge bond on theα-adrenoceptor activity of arylalkylimidazole derivatives, the cardiovascular effects of the molecules were studied in anaesthetized and pithed rats. The compounds studied were 4(5)-substituted imidazole derivatives with a methano, ethano or etheno bridge between the imidazole and the 2-, 2,3- or 2,6-methyl substituted phenyl rings. The hypotensive and bradycardic activities of the molecules in the anaesthetized rat were always reduced byα-hydroxylation and usually augmented byα-methylation of the bridge between the imidazole and phenyl rings. Hydroxylation was associated with a consistent, marked decrease in vasopressor and sympatho-inhibitory activity in the cardiovascular system of the pithed rat, but a methyl moiety as a “bulky substituent” in theα-position of the alkyl bridge did not decrease but even caused an increase inα-adrenoceptor activity in this test system. The detrimental effect ofα-hydroxylation of the compounds atα1- andα2-adrenoceptors supports the notion that the interaction of the imidazoles atα-adrenoceptor is different from that of the classical, noradrenaline-like phenethylamines. The results also suggest that the alkyl bridge between the phenyl and imidazole rings of the imidazoles may contribute directly to the binding process.

The cardiovascular effects of a new compound MPV 295 [4(5)-2-(2,6-dimethylphenyl)ethylimidazole] were studied in both normotensive and spontaneously hypertensive rats (SHR) and in normotensive cats. Intravenous (i.v.) administration of MPV 295 to anaesthetized cats and rats produced an initial increase in blood pressure followed by a long-lasting hypotension and bradycardia. The compound was also effective when administered intracerebroventricularly (i.c.v.) in rats in a dose range 10–100 μg/rat. The antagonism of the hypotensive effect of i.v. injected MPV 295 by i.c.v. administered α-adrenoceptor blocking drugs yohimbine (10 and 30 μg/rat), prazosin (0.5 μg/rat) and 170150 [(imidazolinyl-2)-2-benzodioxane 1–4] (10 μg/rat) suggests that a stimulation of central α-adrenoceptors may be involved in antihypertensive effect of MPV 295. Oral administration of MPV 295 (3 mg/kg) to conscious, chronically cannulated SHR induced a fall in both mean blood pressure (max. 20%) and heart rate (max. 20%). The antihypertensive effect of MPV 295 persisted for longer than 4 h.