Comparison of the behavioral and neurochemical effects of the two optical enantiomers of medetomidine, a selective alpha-2-adrenoceptor agonist.
Medetomidine (MED) is a veterinary sedative whose mode of action is activation of alpha-2 adrenoceptors. Because the carbon atom which separates the two ring systems is methylated, there is a center of stereochemical asymmetry in the molecule. The resulting enantiomers, d-MED and l-MED have recently become available for study. The biological activity of MED, as is now demonstrated in rats in vivo, seems to reside almost exclusively in the d-MED form. Only at extremely high doses (e.g., 10 mg/kg) does l-MED exert any effects, interpreted as alpha-2 adrenoceptor antagonism. In contrast, doses of d-MED as low as 30 micrograms/kg cause sedation, hypothermia and induce neurochemical changes in norepinephrine and 5-hydroxytryptamine metabolism in brain characteristic of alpha-2-agonists (decreases in concentrations of biogenic amine metabolites, turnover and increases in concentration of parent amine). The most sensitive neurochemical indicator of the alpha-2-agonist action of d-MED was the concentration of unconjugated 3-methoxy-4-hydroxy-phenyethylene glycol in rat cerebral spinal fluid, doses of d-MED as low as 10 micrograms/kg caused a significant reduction in this norepinephrine metabolite. Simultaneous administration of the specific alpha-2 adrenoceptor antagonist, atipamezole (1 mg/kg), effectively inhibited the behavioral and most of the neurochemical actions of d-MED (100 micrograms/kg). It is concluded that the enantiomers of MED may be extremely useful in elucidating structure action relationships at alpha-2 adrenoceptors.
Department of Pharmacology & Toxicology, University of Kuopio, Finland.
E
E
MacDonald
M
M
Scheinin
H
H
Scheinin
R
R
Virtanen
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000588:Amines / Q000134:cerebrospinal fluid; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000187:drug effects* / Q000502:physiology; D007093:Imidazoles / Q000494:pharmacology*; D020926:Medetomidine; D008734:Methoxyhydroxyphenylglycol / Q000031:analogs & derivatives / Q000378:metabolism; D008781:Methyltyrosines / Q000494:pharmacology; D051379:Mice; D009638:Norepinephrine / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013237:Stereoisomerism
D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D000588:Amines; D007093:Imidazoles; D008781:Methyltyrosines; C030284:3-methoxy-4-hydroxyphenylglycol sulfate; C022260:alpha-methyltyrosine methyl ester; D008734:Methoxyhydroxyphenylglycol; D020926:Medetomidine; D009638:Norepinephrine