Buspirone analogs. 1. Structure-activity relationships in a series of N-aryl- and heteroarylpiperazine derivatives

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Abstract
A series of analogs of buspirone was synthesized in which modifications were made in the aryl moiety, alkylene chain length and cyclic imide portion of the molecule. These compounds were tested in vitro for their binding affinities to rat brain membrane sites labeled by either the dopamine antagonist [3H]spiperone or the .alpha.1-adrenergic antagonist [3H]WB-4101 [2-[N-(2,6-dimethoxyphenoxyethyl)]aminomethyl-1,4-benzodioxane]. Compounds were tested in vivo for tranquilizing properties and induction of catalepsy. Potency at the [3H]spiperone binding site was affected by alkylene chain length and imide portion composition. Non-ortho substituents on the aryl moiety had effect on [3H]spiperone binding affinity. Structure-activity relationships of ortho substituents demonstrated only modest correlations between the receptor binding data and physical parameters of the substituents. The complex nature of the drug-receptor interactions may be understood in terms of the fit of buspirone to a hypothetical model of the dopamine receptor.