title: Pharmacological characterization of the selective nonpeptide neuropeptide Y Y1 receptor antagonist BIBP 3226.
abstract: The present study was undertaken to investigate the in vitro and in vivo pharmacological profile of the novel, nonpeptide neuropeptide Y (NPY) Y1-selective antagonist, BIBP 3226 [(R)-N2-(diphenylacetyl)-N-[(4-hydroxyphenyl)methyl]-D-arginine-am ide], and a recently described peptidic structure [Ile-Glu-Pro-Orn-Tyr-Arg-Leu-Arg-Tyr-NH2, cyclic (2,4'), (2',4)-diamide]. BIBP 3226 antagonized the NPY Y1 receptor-mediated decrease in the twitch response in the rabbit vas deferens preparation with a pKb value of 6.98 +/- 0.06 (n = 16). It showed no affinity (EC50 > 1 microM) for NPY Y2 receptors in the rat vas deferens. NPY-induced increases in perfusion pressure in the isolated perfused rat kidney and rabbit ear preparations 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 IC50 value of 976 (542-1760) nM. The NPY-induced increase in blood pressure in the pithed rat was inhibited by BIBP 3226 dose-dependently (ED50 = 0.11 +/- 0.03 mg/kg i.v.), whereas no effect of BIBP 3226 (1 mg/kg i.v.) was observed for the noradrenaline-, angiotensin-, endothelin- or vasopressin-induced pressor response. The data presented demonstrate that BIBP 3226 is a competitive and NPY Y1-selective antagonist. The peptidic compound proved to possess high potency for NPY Y1 receptors, but showed both agonistic as well as antagonistic properties.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Dr. Karl Thomae GmbH, Biberach, Germany.
authors.forename: H N
authors.initials: HN
authors.lastname: Doods
authors.forename: W
authors.initials: W
authors.lastname: Wienen
authors.forename: M
authors.initials: M
authors.lastname: Entzeroth
authors.forename: K
authors.initials: K
authors.lastname: Rudolf
authors.forename: W
authors.initials: W
authors.lastname: Eberlein
authors.forename: W
authors.initials: W
authors.lastname: Engel
authors.forename: H A
authors.initials: HA
authors.lastname: Wieland
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D007668:Kidney / Q000098:blood supply / Q000187:drug effects; D008297:Male; D008969:Molecular Sequence Data; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D009478:Neuropeptide Y / Q000031:analogs & derivatives / Q000494:pharmacology; D010477:Perfusion; D011817:Rabbits; D051381:Rats; D011918:Rats, Inbred SHR; D017476:Receptors, Neuropeptide Y / Q000037:antagonists & inhibitors*; D014649:Vas Deferens / Q000187:drug effects / Q000502:physiology
chemical_list: C092926:BIBP 3226; C096170:EXBP 68; D009478:Neuropeptide Y; D017476:Receptors, Neuropeptide Y; D001120:Arginine