EVIDENCE FOR MEDETOMIDINE AS A SELECTIVE AND POTENT AGONIST α2-ADRENORECEPTORS

• 1 The activity on α-adrenoreceptors of medetomidine (±)-4-(α,2,3-trimethylbenzyl)imidazole), an α-methyl derivative of detomidine, has been characterized in vivo and in vitro using detomidine, MPV 207, MPV 295, azepexole, clonidine and xylazine for reference purposes.
• 2 Medetomidine (1–100 μg/kg i.v.) was a hypotensive and bradycardic compound in anaesthetized rats. Furthermore, it induced vasopressor (PD₅₀ 1.7 μg/kg) and sympatho-inhibitory (ID₅₀ 1.6 μg/kg) actions in pithed rats, the effects being antagonized by idazoxan (0.3 mg/kg i.v.) but not by prazosin (0.1 mg/kg i.v.). Medetomidine (30–300 μg/kg i.m.) had an α₂-adrenoreceptor mediated sedative effect on chicks.
• 3 Medetomidine was, overall, more potent than detomidine, MPV 207, clonidine, xylazine, MPV 295 or azepexole in central (sedation in the chick) and peripheral (cardiac presynaptic in the pithed rat) actions on α₂-adrenoreceptors. Clonidine had, however, about an equal potency to medetomidine in the vascular smooth muscle of the pithed rat.
• 4 Like detomidine and MPV 295, medetomidine had no agonistic activity in the rat aortic ring, but high concentrations antagonized methoxamine-induced contractions, giving a pA₂ value of 5.68 for α₁-adrenoreceptor antagonism.
• 5 The overall lipophilicity (log P') of medetomidine in the octanol/buffer (pH 7.4, 24–26°C, HPLC technique) was 2.80.
• 6 In summary, the experimental data suggest that medetomidine is a lipophilic compound with selective α₂-adrenoreceptor-stimulating properties and high potency. It may, therefore, prove to be a suitable pharmacologic tool for interventions in α₂-adrenoreceptor mediated effects in the autonomic nervous system.

     

Peripheral cardiovascular alpha- and beta-adrenergic effects of some hypotensive and bradycardic arylalkyl imidazole derivatives in the rat

In pithed rats, a series of four alkyl bridge analogues of 4(5)-substituted arylalkyl imidazole induced alpha-adrenoceptor-mediated vasoconstriction and inhibition of electrically stimulated tachycardia. These effects were induced in the order of potency clonidine = MPV 207 greater than MPV 295 greater than MPV 304 greater than MPV 390, correlating with the length of the alkyl bridge between the phenyl and imidazole moieties. The peripheral postsynaptic actions of MPV 207 and MPV 304 were attenuated by prazosin (0.1 mg kg-1 i.v.) and yohimbine (1 mg kg-1 i.v.). The pressor responses induced by MPV 295 were antagonized only by yohimbine (0.3 and 1 mg kg-1 i.v.). The peripheral sympathoinhibitory action of these compounds was antagonized by yohimbine (1 mg kg-1 i.v.). In spontaneously beating rat atria, the MPV compounds showed neither agonistic nor antagonistic activity at cardiac postsynaptic alpha- and beta-adrenoceptors. The results indicate that the hypotensive and bradycardic MPV compounds are agonists at peripheral cardiovascular alpha-adrenoceptors. The extension of the alkyl bridge between the phenyl and imidazole moieties reduces their activity at alpha-adrenoceptors. Finally, MPV 295 seems to be a selective agonist of peripheral alpha 2-adrenoceptors in the cardiovascular system of the pithed rat.