title: Inhibition of [3H]clonidine binding to rat brain alpha-adrenoceptors by imidazolidines. Correlation of binding potency and hypotensive activity.
abstract: The inhibition of specifically bound [3H]clonidine (spec. activity 26.7 Ci/mmol; final concentration 0.4 nmol/l) to rat brain membranes was determined for clonidine (2-[2,6-dichlorophenylimino]-2-imidazolidine hydrochloride, Catapresan) and a series of 28 congeneric imidazolidines with different substituents attached to the phenyl moiety and to the bridge nitrogen. The affinity of the compounds for the binding sites labelled by [3H]clonidine greatly depended on these substituents. The potencies of the substances in vitro to inhibit [3H]clonidine binding were correlated with reported hypotensive activities in vivo obtained in anaesthetized rabbits and normotensive rats. Correlation coefficients of r = 0.92 and of r = 0.83, resp., resulted which could be improved upon inclusion of lipophilicity omitting substances with logarithms of octanol/buffer partition coefficient less than -0.5. This finding was explained by the difference in accessibility to the central alpha-adrenoceptor binding sites in vitro and in vivo. Whereas no penetration barrier of importance will affect the process of in vitro binding, the blood/brain barrier has to be crossed before a hypotensive effect can be initiated. The binding affinities of the imidazolidines for central sites identified by [3H]clonidine may provide an indication for potential blood pressure lowering efficacy.
authors.forename: W D
authors.initials: WD
authors.lastname: Bechtel
authors.forename: J
authors.initials: J
authors.lastname: Mierau
authors.forename: P B
authors.initials: PB
authors.lastname: Timmermans
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D001794:Blood Pressure / Q000187:drug effects*; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D003000:Clonidine / Q000378:metabolism*; D007093:Imidazoles / Q000378:metabolism / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D011817:Rabbits; D051381:Rats; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D007093:Imidazoles; D011942:Receptors, Adrenergic, alpha; D003000:Clonidine