Central alpha 2-adrenoceptors are highly stereoselective for dexmedetomidine, the dextro enantiomer of medetomidine.
To determine whether different alpha 2-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-[1(2,3-dimethylphenyl)ethyl]-1H-imidazole), a specific and selective agonist of alpha 2-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 midriatic 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 l-medetomidine might indicate some deviation from strict homogeneity, these experiments demonstrate that the different alpha 2-adrenoceptor-mediated functions have similar stereochemical requirements in the central nervous system.
Savola
J M
JM
Research and Development, Pharmaceuticals, Orion Corporation Farmos, Turku, Finland.
Virtanen
R
R
D000085:Acetates / Q000037:antagonists & inhibitors; D000316:Adrenergic alpha-Agonists / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D000700:Analgesics / Q000378:metabolism; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D006591:Hexobarbital / Q000494:pharmacology; D007093:Imidazoles / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D020926:Medetomidine; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D009184:Mydriatics / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D011942:Receptors, Adrenergic, alpha / Q000378:metabolism*; D012890:Sleep / Q000187:drug effects; D013237:Stereoisomerism
D000085:Acetates; D000316:Adrenergic alpha-Agonists; D000700:Analgesics; D007093:Imidazoles; D009184:Mydriatics; D011942:Receptors, Adrenergic, alpha; D006591:Hexobarbital; D020926:Medetomidine