PHARMACOLOGICAL EVALUATION OF 1229U91, A NOVEL HIGH-AFFINITY AND SELECTIVE NEUROPEPTIDE Y-Y-1 RECEPTOR ANTAGONIST

The physiological role of neuropeptide Y (NPY), peptide YY (PYY) and t heir receptors (Y-1 and Y-2) has been difficult to elucidate mainly du e to the lack of selective and high-affinity antagonists. Recently, Bu rroughs Wellcome disclosed a series of cyclic peptides, including the compound 1229U91, which were reported to be selective NPY receptor ant agonists (PCT Publication No. WO 94/00486). The objective of this stud y was to evaluate the pharmacological properties of 1229U91. In radiol igand binding studies, 1229U91 displaced specifically bound [I-125]PYY from SK-N-MC cells (Y-1 receptors) and SK-N-BE(2) cells (Y-2 receptor s) yielding pK(i) +/- S.E.M. estimates of 10.9 +/- 0.2 and 7.9 +/- 0.2 , respectively. In the isolated perfused kidney of rat (Y-1 receptor a ssay), NPY (10-1000 ng, bolus injection) evoked concentration-dependen t increases in perfusion pressure (EC(50) = 54.5 ng). In this assay, 1 229U91 (1, 10 and 100 nM) produced concentration-dependent dextral dis placement of the concentration-effect curve to NPY, The antagonism was surmountable at 1 nM 1229U91 (apparent pA(2) estimate +/- S.E.M. = 9. 3 +/- 0.4). At concentrations of 10 and 100 nM, 1229U91 produced signi ficant depression of the maximum response to NPY (36 and 67%, respecti vely). In the vas deferens of rat (Y-2 receptor assay), 1229U91 (3 mu M) had no effect on NPY-induced inhibition of electrically evoked twit ch response. In pithed rats, 1229U91 (0.3, 1 and 3 mu g/kg/min i.v.) p roduced dose-dependent dextral displacement of the presser dose-respon se curve to NPY yielding dose-ratio estimates of 2.4, 25.4 and 57.5, r espectively. 1229U91 (3 mu g/kg/min i.v.) had no effect on the presser responses to norepinephrine or angiotensin II. When administered as a single i.v. bolus injection, 1229U91 (0.01-1 mg/kg i.v.) produced dos e-dependent inhibition of the presser response to NPY. At 0.3 and 1 mg /kg i.v., the inhibitory effects lasted for more than 95 min. The data suggest that 1229U91 is a high-affinity and selective Y-1 receptor an tagonist and would be of value for investigating the physiological rol e of NPY and PW in vitro and in vivo.