title: Vascular pharmacology of BIIE0246, the first selective non-peptide neuropeptide Y Y(2) receptor antagonist, in vivo.
abstract: BIIE0246, a recently introduced non-peptide neuropeptide Y (NPY) Y(2) receptor antagonist, was pharmacologically characterized in vivo, on vascular responses evoked in the anaesthetized pig. The NPY Y(2) receptor agonist N-acetyl[Leu(28)Leu(31)]NPY(24-36) evoked dose-dependent vasoconstriction in spleen. These vascular responses were potently and dose-dependently antagonized by BIIE0246. Significant inhibition was seen already at 1 nmol kg(-1), whereas at 100 nmol kg(-1) of BIIE0246 these responses were completely abolished. The ID(50) value for this antagonism was 2.1 nmol kg(-1). Peptide YY (PYY) evoked dose-dependent vasoconstriction in both kidney and spleen, vascular responses mediated by the NPY Y(1) receptor and both NPY Y(1) and Y(2) receptors, respectively. Only the splenic response was inhibited by BIIE0246, the effect of which reached significance at 1 nmol kg(-1). Already 30 min after the last dose of BIIE0246 there was a significant recovery of the PYY-evoked splenic vasoconstriction, and a further 60 min later, this response was no longer significantly inhibited compared to control. BIIE0246 (100 nmol kg(-1)) did not affect renal and splenic vasoconstrictor responses either to the NPY Y(1) receptor agonist [Leu(31)Pro(34)]NPY, the alpha(1)-adrenoceptor agonist phenylephrine, the P2X(1)-purinoceptor agonist alpha,beta-methylene ATP or angiotensin II, demonstrating both selectivity and specificity for the NPY Y(2) receptor in vivo. It is concluded that BIIE0246 is a highly potent and selective NPY Y(2) receptor antagonist, albeit with rather short duration of action, in vivo. BIIE0246 thus represents the first interesting tool for studies on NPY Y(2) receptor-mediated transmission in vivo.
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institute, S-17177 Stockholm, Sweden. rickard.malmstrom@fyfa.ki.se
authors.forename: R E
authors.initials: RE
authors.lastname: Malmström
mesh_terms: D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D001552:Benzazepines / Q000494:pharmacology*; D001783:Blood Flow Velocity / Q000187:drug effects*; D001794:Blood Pressure / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D007668:Kidney / Q000098:blood supply; D008297:Male; D009478:Neuropeptide Y / Q000031:analogs & derivatives / Q000494:pharmacology; D019894:Peptide YY / Q000494:pharmacology; D017476:Receptors, Neuropeptide Y / Q000819:agonists / Q000037:antagonists & inhibitors*; D013154:Spleen / Q000098:blood supply; D013552:Swine; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: D001552:Benzazepines; D009478:Neuropeptide Y; D017476:Receptors, Neuropeptide Y; D019894:Peptide YY; C062259:neuropeptide Y, Leu(31)-Pro(34)-; D001120:Arginine; C403256:BIIE 0246