S41744, a dual neurokinin (NK)1 receptor antagonist and serotonin (5-HT) reuptake inhibitor with potential antidepressant properties: a comparison to aprepitant (MK869) and paroxetine.
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.
Millan
Mark J
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
Dekeyne
Anne
A
Gobert
Alain
A
Mannoury la Cour
Clotilde
C
Brocco
Mauricette
M
Rivet
Jean-Michel
JM
Di Cara
Benjamin
B
Lejeune
Françoise
F
Cremers
Thomas I
TI
Flik
Gunnar
G
de Jong
Trynke R
TR
Olivier
Berend
B
de Nanteuil
Guillaume
G
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology / Q000627:therapeutic use / Q000633:toxicity; D000077608:Aprepitant; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D005849:Gerbillinae; D006168:Guinea Pigs; D006801:Humans; D007189:Indans / Q000494:pharmacology* / Q000627:therapeutic use* / Q000633:toxicity; D008297:Male; D051379:Mice; D009025:Morpholines / Q000494:pharmacology* / Q000627:therapeutic use* / Q000633:toxicity; D009043:Motor Activity / Q000187:drug effects; D064729:Neurokinin-1 Receptor Antagonists; D010147:Pain Measurement; D017374:Paroxetine / Q000494:pharmacology* / Q000627:therapeutic use* / Q000633:toxicity; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use* / Q000633:toxicity; D011247:Pregnancy; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins / Q000187:drug effects* / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology / Q000627:therapeutic use / Q000633:toxicity; D013312:Stress, Physiological / Q000187:drug effects
D000928:Antidepressive Agents; D000077608:Aprepitant; D048049:Extracellular Signal-Regulated MAP Kinases; D007189:Indans; D009025:Morpholines; D064729:Neurokinin-1 Receptor Antagonists; D017374:Paroxetine; D010879:Piperazines; D018040:Receptors, Neurokinin-1; D012701:Serotonin; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; C553966:2-piperazin-1-ylindan-2-carboxylic acid (3-chloro-5-fluorobenzyl)methylamide