title: Cardiovascular and sedative alpha-adrenoceptor effects of detomidine-like arylalkyl imidazoles and associated derivatives.
abstract: The effects of detomidine (4-[(2,3-dimethylphenyl)methyl]-1H-imidazole, Domosedan) and its congeners, MPV compounds, are evaluated in the cardiovascular system and related to their sedative action using clonidine and xylazine for reference purposes. The structure of the MPV compounds had been modified with methyl substituents in the phenyl ring, with differing lengths in the alkyl bridge, and with variations in the imidazole terminus. The lipophilicity of the test compounds had been estimated in terms of apparent partition coefficients in the octanol/buffer (pH 7.4, 24-26 degrees C) using the HPLC technique. The lipophilicity of the MPV compounds was found to be higher than for either clonidine or xylazine, suggesting a more rapid penetration into the central nervous system. Some of these 21 MPV compounds were hypotensive and bradycardic in anaesthetized rats. Interestingly a number of these MPV compounds were only bradycardic but not clearly hypotensive after i.v. administration to anaesthetized rats, this being most obvious in the case of the 2,5-dimethylphenyl derivative MPV 867. A further characteristic distinguishing between the central and peripheral alpha-adrenoceptors regulating cardiovascular tone was a distinct inability of some derivatives active at peripheral cardiac presynaptic (pithed rats) and central (young chicks) alpha 2-adrenoceptors to reduce blood pressure in anaesthetized rats. The sedative action of the compounds after i.m. injection into 2- to 5-day-old chicks was in general related to their central hypotensive and bradycardic effect in anaesthetized rats, and with peripheral vasopressor and sympatho-inhibitory activity in pithed rats.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Pharmacology, University of Oulu, Finland.
authors.forename: J M
authors.initials: JM
authors.lastname: Savola
authors.forename: H
authors.initials: H
authors.lastname: Ruskoaho
authors.forename: J S
authors.initials: JS
authors.lastname: Salonen
authors.forename: J
authors.initials: J
authors.lastname: Puurunen
authors.forename: A
authors.initials: A
authors.lastname: Karjalainen
authors.forename: K
authors.initials: K
authors.lastname: Kurkela
authors.forename: N T
authors.initials: NT
authors.lastname: Kärki
mesh_terms: D000758:Anesthesia; D000818:Animals; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002645:Chickens; D003655:Decerebrate State; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D007093:Imidazoles / Q000032:analysis / Q000494:pharmacology*; D008297:Male; D004856:Postural Balance / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects*; D012018:Reflex / Q000187:drug effects
chemical_list: D006993:Hypnotics and Sedatives; D007093:Imidazoles; D011942:Receptors, Adrenergic, alpha; C041255:detomidine