Central α2-adrenoceptors are highly stereoselective for dexmedetomidine, the dextro enantiomer of medetomidine

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Abstract

To determine whether different α2-adrenoceptor-mediated functions have different stereochemical requirements in the central nervous system, we studied the pharmacological activities of the purified optical enantiomers of medetomidine (dl-4-[l(2,3-dimethylphenyl)ethyl]-1H-imidazole), a specific and selective agonist of α2-adrenoceptors. We found that dexmedetomidine (the dextro enantiomer) had the pharmacological activity of medetomidine. Dexmedetomidine had hypotensive and bradycardic actions in anaesthetized rats as well as sedative (decreased spontaneous locomotor activity and prolonged sleep induced by hexobarbital in rats), analgesic (attenuated a writhing response induced by acetic acid in mice) and mydriatic actions in rats. The potency of dexmedetomidine was slightly greater than that of medetomidine. 1-Medetomidine was generally without pharmacological activity, but it showed some sedative and analgesic properties at high doses. Although the findings obtained with 1-medetomidine might indicate some deviation from strict homogeneity, these experiments demonstrate that the different α2-adrenoceptor-mediated functions have similar stereochemical requirements in the central nervous system.

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      Medetomidine (4-[1-(2,3- dimethylphenyl)ethyl]-1H-imidazole) is an α2-adrenoreceptor agonist, which is used as an analgesic and anesthetic drug in veterinary medicine [28]. The pharmacological activity has been attributed mainly to the dextrorotary (S)-enantiomer dexmedetomidine [29], which has been developed for human use as a sedative in anesthesia management in surgery and in intensive care medicine [30]. In the process of the development of a CE-based assay for the determination of the stereochemical purity of dexmedetomidine using CDs as chiral selectors [31], different enantiomer migration orders depending on the CD were observed.

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