Vascular pharmacology of BIIE0246, the first selective non‐peptide neuropeptide Y Y 2 receptor antagonist, in vivo

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 α 1 ‐adrenoceptor agonist phenylephrine, the P2X 1 ‐purinoceptor agonist α,β‐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 .British Journal of Pharmacology (2001) 133 , 1073–1080; doi: 10.1038/sj.bjp.0704171