The present organ chamber and receptor binding studies were designed to evaluate the alpha adrenoceptor subtype (alpha-1 vs. alpha-2) and tissue selectivity of buspirone and the related compounds, gepirone, isapirone and 1-(2-pyrimidinyl)-piperazine (a metabolite of buspirone). Buspirone, gepirone and isapirone were found to possess weak alpha-1 adrenoceptor affinity (relative to prazosin) but significant and selective alpha-1 adrenoceptor intrinsic efficacy (relative to norepinephrine, phenylephrine and ST-587), which was expressed in a tissue- and species-dependent manner. The rank order for alpha-1 adrenoceptor affinity (isapirone greater than buspirone approximately equal to gepirone) was different from the rank order for alpha-1 adrenoceptor intrinsic efficacy (buspirone greater than gepirone greater than isapirone). The tissues that were the most responsive to norepinephrine and ST-587 (i.e., rat and rabbit aorta) were the same tissues in which the intrinsic efficacy of buspirone was expressed. In contrast, 1-(2-pyrimidinyl)-piperazine was inactive at alpha-1 adrenoceptors. Although no alpha-2 adrenoceptor intrinsic efficacy was observed for any of the compounds, isapirone and 1-(2-pyrimidinyl)-piperazine displayed weak alpha-2 adrenoceptor affinity (relative to rauwolscine). Recent studies have shown buspirone to have an effect on central and peripheral monoaminergic mechanisms. The demonstration in the present study that buspirone and related compounds display significant alpha adrenoceptor activity suggests that alpha adrenoceptor involvement should be considered as a potential contributing factor in the central nervous system and/or peripheral activity of this class of compounds.