Ipsapirone and gepirone, analogs of buspirone, a newly developed antianxiety agent, form 1-(2-pyrimidinyl)-piperazine (PmP) during their biotransformation in rats. After oral administration (10 mg/kg) of a parent drug, e.g. ipsapirone or gepirone, the metabolite appears in significant amounts in plasma, with maximal concentrations of 0.9 and 1.4 nmol/ml respectively. The metabolite half-life ranged from about 140 to 200 min. Ipsapirone is eliminated more slowly than gepirone, with a half-life of about 100 and 30 min, respectively. The metabolite to parent drug ratios for the areas under the plasma concentration-time curve (AUC) were 1 for ipsapirone and 14 for gepirone. PmP (0.5-2 mg/kg p.o), ipsapirone, gepirone and buspirone (5-20 mg/kg p.o.) dose dependently antagonized the slowing of gastrointestinal transit induced by clonidine 0.1 mg/kg s.c. The doses inhibiting the antitransit effect of clonidine by 50% were 0.8 mg/kg for PmP, 14 mg/kg for ipsapirone and 9 mg/kg for both gepirone and buspirone. Analysis of small intestinal longitudinal muscle of rats given the ED50 of PmP, ipsapirone, gepirone, buspirone showed that PmP concentrations in the longitudinal muscle (with attached myenteric plexus) fell within a relatively narrow range and were consistent with the appropriate transit scores. The plasma was also tested for anticlonidine activity. These data indicate that PmP formation is a pharmacologically significant metabolic process for the buspirone-related drugs, ipsapirone and gepirone, and that this metabolite is responsible for the alpha 2-adrenoceptor blocking activity exerted by these drugs in vivo in the rat.