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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Millan, Mark J. Dekeyne, Anne Gobert, Alain Mannoury la Cour, Clotilde Brocco, Mauricette Rivet, Jean-Michel Di Cara, Benjamin Lejeune, Françoise Cremers, Thomas I. Flik, Gunnar de Jong, Trynke R. Olivier, Berend de Nanteuil, Guillaume |
| Description | Country affiliation: France Author Affiliation: Millan MJ ( Psychopharmacology Department, Institut de Recherches Servier, Centre de Recherches de Croissy, 125 Chemin de Ronde, 78290 Croissy-sur-Seine, France. mark.millan@fr.netgrs.com) |
| Abstract | Though $neurokinin_{1}$ $(NK_{1})$ receptors are implicated in depressed states and their treatment, selective antagonists have disappointed in clinical trials. Accordingly, we designed a novel ligand, S41744 (2-piperazin-1-yl-indan-2-carboxylic-acid-(3-chloro-5-fluoro-benzyl)-methyl-amide), which both blocks $NK_{1}$ receptors and interferes with serotonin (5-HT) reuptake. S41744 mimicked the selective antagonist aprepitant in binding human $(h)NK_{1}$ receptors and in antagonising Substance-P-mediated Extracellular-Regulated-Kinase phosphorylation $(pK_{B},$ 7.7). Further, it dose-dependently (0.63–40.0 mg/kg, i.p.) displaced ex vivo $[^{3}H]-[Sar^{9},Met(O_{2})^{11}]-Substance$ P binding to gerbil striatum, attenuated formalin-induced hind-paw licking in gerbils, and antagonised locomotion induced by i.c.v. administration of the $NK_{1}$ agonist GR73632 to guinea pigs. Like paroxetine, S41744 recognised h5-HT transporters, reduced synaptosomal uptake of 5-HT $(pK_{B},$ 7.9), and dose-dependently (0.63–10.0 mg/kg) elevated dialysis levels of 5-HT in the hippocampus and frontal cortex of freely-moving guinea pigs. Further, S41744 increased extracellular levels of 5-HT in frontal cortex and hippocampus of rats to a greater extent than paroxetine, and its inhibitory influence upon serotonergic perikarya was blunted relative to its affinity for 5-HT transporters. S41744 more potently blocked stress-induced vocalizations in guinea pigs than aprepitant and paroxetine, and it was active in forced-swim and marble-burying procedures of putative antidepressant properties in mice. While aprepitant displayed anxiolytic actions in stress-induced foot-tapping and social interaction tests in gerbils, paroxetine was anxiogenic and S41744 “neutral”, reflecting balanced $NK_{1}$ antagonism and suppression of 5-HT reuptake. Moreover, S41744 shared anxiolytic actions of aprepitant in the rat Vogel Conflict Test. In conclusion, S41744 is an innovative $NK_{1}$ antagonist/5-HT reuptake inhibitor justifying further evaluation for treatment of stress-related disorders. |
| File Format | HTM / HTML |
| ISSN | 0924977X |
| Issue Number | 9 |
| Volume Number | 20 |
| e-ISSN | 18737862 |
| Journal | European Neuropsychopharmacology |
| Language | English |
| Publisher | Elsevier |
| Publisher Date | 2010-09-01 |
| Publisher Place | Netherlands |
| Access Restriction | One Nation One Subscription (ONOS) |
| Subject Keyword | Discipline Psychopharmacology Indans Pharmacology Therapeutic Use Morpholines Neurokinin-1 Receptor Antagonists Paroxetine Piperazines Serotonin Plasma Membrane Transport Proteins Drug Effects Animals Antidepressive Agents Toxicity Behavior, Animal Brain Metabolism Extracellular Signal-regulated Map Kinases Female Gerbillinae Guinea Pigs Humans Male Mice Motor Activity Pain Measurement Pregnancy Radioligand Assay Rats Rats, Wistar Receptors, Neurokinin-1 Serotonin Serotonin Uptake Inhibitors Stress, Physiological Comparative Study Journal Article Research Support, Non-u.s. Gov't |
| Content Type | Text |
| Resource Type | Article |
| Subject | Neurology Biological Psychiatry Neurology (clinical) Pharmacology Pharmacology (medical) Psychiatry and Mental Health |
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