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Characterization of RO4583298 as a novel potent, dual antagonist with in vivo activity at tachykinin NK₁ and NK₃ receptors.

AbstractBACKGROUND AND PURPOSE:
Clinical results of osanetant and talnetant (selective-NK₃ antagonists) indicate that blocking the NK₃ receptor could be beneficial for the treatment of schizophrenia. The objective of this study was to characterize the in vitro and in vivo properties of a novel dual NK₁/NK₃ antagonist, RO4583298 (2-phenyl-N-(pyridin-3-yl)-N-methylisobutyramide derivative).
EXPERIMENTAL APPROACH:
RO4583298 in vitro pharmacology was investigated using radioligand binding ([³H]-SP, [³H]-osanetant, [³H]-senktide), [³H]-inositol-phosphate accumulation Schild analysis (SP- or [MePhe⁷]-NKB-induced) and electrophysiological studies in guinea-pig substantia nigra pars compacta (SNpc). The in vivo activity of RO4583298 was assessed using reversal of GR73632-induced foot tapping in gerbils (GFT; NK₁) and senktide-induced tail whips in mice (MTW; NK₃).
KEY RESULTS:
RO4583298 has a high-affinity for NK₁ (human and gerbil) and NK₃ (human, cynomolgus monkey, gerbil and guinea-pig) receptors and behaves as a pseudo-irreversible antagonist. Unusually it binds with high-affinity to mouse and rat NK₃, yet with a partial non-competitive mode of antagonism. In guinea-pig SNpc, RO4583298 inhibited the senktide-induced potentiation of spontaneous activity of dopaminergic neurones with an apparent non-competitive mechanism of action. RO4583298 (p.o.) robustly blocked the GFT response, and inhibited the MTW.
CONCLUSIONS AND IMPLICATIONS:
RO4583298 is a high-affinity, non-competitive, long-acting in vivo NK₁/NK₃ antagonist; hence providing a useful in vitro and in vivo pharmacological tool to investigate the roles of NK₁ and NK₃ receptors in psychiatric disorders.
AuthorsP Malherbe, F Knoflach, M C Hernandez, T Hoffmann, P Schnider, R H Porter, J G Wettstein, T M Ballard, W Spooren, L Steward
JournalBritish journal of pharmacology (Br J Pharmacol) Vol. 162 Issue 4 Pg. 929-46 (Feb 2011) ISSN: 1476-5381 [Electronic] England
PMID21039418 (Publication Type: Journal Article)
Copyright© 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.
Chemical References
  • 2-(3,5-bis-trifluoromethylphenyl)-N-(4-(4-fluoro-2-methylphenyl)-6-(3-hydroxy-2-hydroxymethylpyrrolidin-1-yl)pyridin-3-yl)-N-methylisobutyramide
  • Amides
  • Aminopyridines
  • Antipsychotic Agents
  • Benzeneacetamides
  • Ligands
  • Neurokinin-1 Receptor Antagonists
  • Pyridines
  • Receptors, Neurokinin-1
  • Receptors, Neurokinin-3
  • Substance P
  • Inositol
Topics
  • Action Potentials (drug effects)
  • Amides (metabolism, pharmacokinetics, pharmacology)
  • Aminopyridines
  • Animals
  • Antipsychotic Agents (metabolism, pharmacokinetics, pharmacology)
  • Benzeneacetamides
  • Dose-Response Relationship, Drug
  • Female
  • Gerbillinae
  • Guinea Pigs
  • HEK293 Cells
  • Humans
  • In Vitro Techniques
  • Inositol (metabolism)
  • Ligands
  • Macaca fascicularis
  • Male
  • Mesencephalon (drug effects, physiology)
  • Mice
  • Neurokinin-1 Receptor Antagonists
  • Neurons (drug effects, physiology)
  • Phosphorylation (drug effects)
  • Pyridines (metabolism, pharmacokinetics, pharmacology)
  • Rats
  • Receptors, Neurokinin-1 (agonists, genetics, metabolism)
  • Receptors, Neurokinin-3 (agonists, antagonists & inhibitors, genetics, metabolism)
  • Schizophrenia (drug therapy)
  • Substance P (analogs & derivatives, antagonists & inhibitors)
  • Substantia Nigra (drug effects, physiology)

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