PHARMACOLOGICAL CHARACTERIZATION OF THE SELECTIVE NONPEPTIDE NEUROPEPTIDE-Y Y1 RECEPTOR ANTAGONIST BIBP-3226

The present study was undertaken to investigate the in vitro and in vi vo pharmacological profile of the novel, nonpeptide neuropeptide Y (NP Y) Y1-selective antagonist, BIBP 3226 yl)-N-[(4-hydroxyphenyl)methyl]- D-arginine-amide}, and a recently described peptidic structure [Ile-Gl u-Pro-Orn-Tyr-Arg-Leu-Arg-Tyr-NH2, cyclic (2,4'), (2',4)-diamide]. BIB P 3226 antagonized the NPY Y1 receptor-mediated decrease in the twitch response in the rabbit vas deferens preparation with a pK(b) value of 6.98 +/- 0.05 (n = 16). It showed no affinity (EC(50) > 1 mu M) for N PY Y2 receptors in the rat vas deferens. NPY-induced increases in perf usion pressure in the isolated perfused rat kidney and rabbit ear prep arations were antagonized with IC50 values of 26.8 +/- 4.5 (n = 4) and 214 +/- 30 nM (n = 4), respectively. The NPY-mediated potentiation of the noradrenaline elicited increase in perfusion pressure in the rat mesenteric bed was antagonized with an lC(50) value of 976 (542-1760) nM. The NPY-induced increase in blood pressure in the pithed rat was i nhibited by BIBP 3226 dose-dependently (ED(50) = 0.11 +/- 0.03 mg/kg i .v.), whereas no effect of BIBP 3226 (1 mg/kg i.v.) was observed for t he noradrenaline-, angiotensin-, endothelin- or vasopressin-induced pr esser response. The data presented demonstrate that BIBP 3226 is a com petitive and NPY Y1-selective antagonist. The peptidic compound proved to possess high potency for NPY Y1 receptors, but showed both agonist ic as well as antagonistic properties. BIBP 3226 in doses up to 3 mg/k g i.v. did not lower brood pressure in conscious spontaneously hyperte nsive rats. This might indicate that NPY or the NPY Y1 receptor do not play a relevant role in the maintenance of blood pressure in the spon taneously hypertensive rat.