Two affinities for a single antagonist at the neuronal NK1 tachykinin receptor: evidence from quantitation of receptor endocytosis

Br J Pharmacol. 1999 Jan;126(1):131-6. doi: 10.1038/sj.bjp.0702285.

Abstract

1. In smooth muscle contractility assays, many NK1 receptor (NK1r) antagonists inhibit responses to the neurotransmitter, substance P (SP), and its analogue, septide, with markedly different potency, leading to the proposal that there is a septide-preferring receptor related to the NK1r. 2. We used fluorescence immunohistochemistry and confocal microscopy to visualize agonist-induced NK1r endocytosis and analyse agonist/antagonist interactions at native NK1r in neurons of the myenteric plexus of guinea-pig ileum. 3. SP and septide gave sigmoid log concentration-response curves and were equipotent in inducing NK1r endocytosis. 4. The NK1r antagonists, CP-99994 (2S,3S)-3-(2-methoxybenzyl)amino-2-phenylpiperidine dihydrochloride and MEN-10581, cyclo(Leu,[CH2NH]Lys(benzyloxycarbonyl)-Gln-Trp-Phe-betaAla) were both more potent in inhibiting endocytosis (50 x and 8 x greater respectively) against septide than against SP. 5. The results suggest that SP and septide interact differently with the NK1r, and that a single antagonist can exhibit different affinities at a single NK1r population, depending on the agonist with which it competes. Thus it may not be necessary to posit a separate septide-preferring tachykinin receptor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding, Competitive
  • Dose-Response Relationship, Drug
  • Endocytosis / drug effects
  • Female
  • Fluorescence
  • Guinea Pigs
  • Ileum / drug effects
  • Ileum / metabolism
  • In Vitro Techniques
  • Male
  • Microscopy, Confocal
  • Neurokinin-1 Receptor Antagonists
  • Neurons / drug effects
  • Neurons / metabolism*
  • Peptides, Cyclic / pharmacology
  • Piperidines / pharmacology
  • Receptors, Neurokinin-1 / metabolism*
  • Receptors, Neurokinin-3 / antagonists & inhibitors
  • Receptors, Neurokinin-3 / metabolism
  • Substance P / analogs & derivatives
  • Substance P / pharmacology

Substances

  • MEN 10581
  • Neurokinin-1 Receptor Antagonists
  • Peptides, Cyclic
  • Piperidines
  • Receptors, Neurokinin-1
  • Receptors, Neurokinin-3
  • 3-(2-methoxybenzylamino)-2-phenylpiperidine
  • Substance P
  • SR 142801