Non-competitive binding of the nonpeptide antagonist BIBP3226 to rat forebrain neuropeptide Y1 receptors

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[3H]Neuropeptide Y labelled neuropeptide Y receptors in rat forebrain membranes as a homogenous class of high-affinity sites. Between 80 and 85% of these receptors showed high affinity for Y1-selective antagonists such as (R)-N2-(diphenylacetyl)-N-[(4-hydroxyphenyl)methyl]-D-arginine amide (BIBP3226). While competitive in functional studies, BIBP3226 produced parallel shifts of the Scatchard plots of [3H]neuropeptide Y saturation binding in rat forebrain membranes. Mechanisms which are routinely invoked to explain non-competitive binding do not apply to BIBP3226. Wash-out experiments, involving successive treatment of the membranes with BIBP3226, buffer (wash-out step) and [3H]neuropeptide Y, argue against irreversible or a pseudo-irreversible binding of the antagonist. Allosteric inhibition is also unlikely since BIBP3226 did not affect the rate of dissociation of [3H]neuropeptide Y in isotope dilution experiments. The non-hydrolyzable guanine nucleotide, 5'-guanylylimidodiphosphate (Gpp(NH)p), abolished the binding of [3H]neuropeptide Y and increased its rate of dissociation in isotope dilution experiments. This suggests that the initial [3H]neuropeptide Y-receptor association is a low affinity process and that the observed binding of [3H]neuropeptide Y is related to the formation of a ternary [3H]neuropeptide Y-receptor-G protein complex. Two- or even multistate models (in which BIBP3226 could potentially behave as an inverse agonist) could therefore be needed to explain the non-competitive antagonism of BIBP3226 in broken cell preparations.

Original languageEnglish
Pages (from-to)275-284
Number of pages10
JournalEuropean Journal of Pharmacology
Issue number2-3
Publication statusPublished - 23 Jul 1997


  • Animals
  • Arginine
  • Binding, Competitive
  • Guanylyl Imidodiphosphate
  • Half-Life
  • In Vitro Techniques
  • Membranes
  • Nerve Tissue Proteins
  • Neuropeptide Y
  • Prosencephalon
  • Proteins
  • Radioligand Assay
  • Rats
  • Receptors, Neuropeptide Y
  • Research Support, Non-U.S. Gov't

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