The physiological role of neuropeptide Y (NPY), peptide YY (PYY) and their receptors (Y1 and Y2) has been difficult to elucidate mainly due to the lack of selective and high-affinity antagonists. Recently, Burroughs Wellcome disclosed a series of cyclic peptides, including the compound 1229U91, which were reported to be selective NPY receptor antagonists (PCT Publication No. WO 94/00486). The objective of this study was to evaluate the pharmacological properties of 1229U91. In radioligand binding studies, 1229U91 displaced specifically bound [125I]PYY from SK-N-MC cells (Y1 receptors) and SK-N-BE(2) cells (Y2 receptors) yielding pKi +/- S.E.M. estimates of 10.9 +/- 0.2 and 7.9 +/- 0.2, respectively. In the isolated perfused kidney of rat (Y1 receptor assay), NPY (10-1000 ng, bolus injection) evoked concentration-dependent increases in perfusion pressure (EC50 = 54.5 ng). In this assay, 1229U91 (1, 10 and 100 nM) produced concentration-dependent dextral displacement of the concentration-effect curve to NPY. The antagonism was surmountable at 1 nM 1229U91 (apparent pA2 estimate +/- S.E.M. = 9.3 +/- 0.4). At concentrations of 10 and 100 nM, 1229U91 produced significant depression of the maximum response to NPY (36 and 67%, respectively). In the vas deferens of rat (Y2 receptor assay), 1229U91 (3 microM) had no effect on NPY-induced inhibition of electrically evoked twitch response. In pithed rats, 1229U91 (0.3, 1 and 3 micrograms/kg/min i.v.) produced dose-dependent dextral displacement of the pressor dose-response curve to NPY yielding dose-ratio estimates of 2.4, 25.4 and 57.5, respectively. 1229U91 (3 micrograms/kg/min i.v.) had no effect on the pressor responses to norepinephrine or angiotensin II.(ABSTRACT TRUNCATED AT 250 WORDS)