Relationships between structure and alpha-adrenergic receptor affinity of clonidine and some related cyclic amidines.

The inhibition of specific [3H]clonidine binding to alpha-adrenergic receptors in rat brain has been studied for 43 compounds structurally related to clonidine. Oxymetazoline was found to be the most potent compound in displacing [3H]clonidine from its binding sites. 2-Methylimidazoline, 1,2,3,5-tetrahydroimidazo[2,1-b]quinazoline and heterocyclic N-methyl-substituted compounds showed no affinity at all for [3H]clonidine receptor sites. There was a good correlation between hypotensive activity and alpha 2-adrenergic receptor affinity to some 2-(phenylamino)imidazolidines. Parallelisms between Ki's and pharmacological activities were also observed for other compounds. Apparent structural requirements for alpha 2-receptor affinity were the presence of an aromatic moiety and a N-hydrogen in the heterocyclic ring. Ortho substitution in the phenyl ring was necessary for high affinity. Compounds with an oxazolidine ring had approximately similar affinities for the [3H]clonidine binding sites compared with the corresponding imidazolines (except for the 2,6-dichlorophenyl-substituted compound) whereas the pyrrolidine derivatives showed a 10-fold weaker affinity. [3H]Clonidine sites showed a homogeneous character. KD values from saturation and displacement experiments were in good agreement with one another (2.6 and 2.7 nM, respectively) and with values in the literature.