Abstract | BACKGROUND 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.
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Authors | P Malherbe, F Knoflach, M C Hernandez, T Hoffmann, P Schnider, R H Porter, J G Wettstein, T M Ballard, W Spooren, L Steward |
Journal | British journal of pharmacology
(Br J Pharmacol)
Vol. 162
Issue 4
Pg. 929-46
(Feb 2011)
ISSN: 1476-5381 [Electronic] England |
PMID | 21039418
(Publication Type: Journal Article)
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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
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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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