| Article ID | Journal | Published Year | Pages | File Type |
|---|---|---|---|---|
| 319718 | European Neuropsychopharmacology | 2010 | 23 Pages |
Though neurokinin1 (NK1) 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 NK1 receptors and interferes with serotonin (5-HT) reuptake. S41744 mimicked the selective antagonist aprepitant in binding human (h)NK1 receptors and in antagonising Substance-P-mediated Extracellular-Regulated-Kinase phosphorylation (pKB, 7.7). Further, it dose-dependently (0.63–40.0 mg/kg, i.p.) displaced ex vivo [3H]-[Sar9,Met(O2)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 NK1 agonist GR73632 to guinea pigs. Like paroxetine, S41744 recognised h5-HT transporters, reduced synaptosomal uptake of 5-HT (pKB, 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 NK1 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 NK1 antagonist/5-HT reuptake inhibitor justifying further evaluation for treatment of stress-related disorders.
