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Inhibition of [3H]clonidine binding to rat brain alpha-adrenoceptors by imidazolidines. Correlation of binding potency and hypotensive activity.

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.