Vascular pharmacology of BIIE0246 the first selective non-peptide neuropeptide Y Y2 receptor antagonist in vivo

摘要

class="enumerated" style="list-style-type:decimal">BIIE0246, a recently introduced non-peptide neuropeptide Y (NPY) Y2 receptor antagonist, was pharmacologically characterized in vivo, on vascular responses evoked in the anaesthetized pig.The NPY Y2 receptor agonist N-acetyl[Leu²⁸Leu³¹]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 ID50 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 Y1 receptor and both NPY Y1 and Y2 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 Y1 receptor agonist [Leu³¹Pro³⁴]NPY, the α1-adrenoceptor agonist phenylephrine, the P2X1-purinoceptor agonist α,β-methylene ATP or angiotensin II, demonstrating both selectivity and specificity for the NPY Y2 receptor in vivo.It is concluded that BIIE0246 is a highly potent and selective NPY Y2 receptor antagonist, albeit with rather short duration of action, in vivo. BIIE0246 thus represents the first interesting tool for studies on NPY Y2 receptor-mediated transmission in vivo.