SSR240600 [(<i>R</i>)-2-(1-{2-[4-{2-[3,5-Bis(trifluoromethyl)phenyl]acetyl}-2-(3,4-dichlorophenyl)-2-morpholinyl]ethyl}-4-piperidinyl)-2-methylpropanamide], a Centrally Active Nonpeptide Antagonist of the Tachykinin Neurokinin 1 Receptor: II. Neurochemical and Behavioral Characterization

Steinberg, R.; Alonso, Richard; Rouquier, L.; Desvignes, Christophe; Michaud, Jean-Claude; Cudennec, Annie; Jung, Mireille; Simiand, Jacques; Griebel, Guy; Emonds‐Alt, Xavier; Fur, G. Le; Soubrié, Philippe

doi:10.1124/jpet.102.040279

Cited by 37 publications

(17 citation statements)

References 38 publications

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“…The increased activation of LC neurons following local application of SP is associated with elevated levels of NE in terminal areas [137,138]. An NK 1 receptor antagonist (GR205171) has been reported to elicit a dose dependent elevation in dialysate levels of NE in rat frontal cortex consistent with the reported increase in LC firing in this study [114].…”

Section: Locus Coeruleussupporting

confidence: 60%

“…While SP is excitatory, the effect of NK 1 receptor antagonists on basal firing of LC neurons is controversial. In vivo, antagonists have been shown to be without effect on basal firing rates in rats [139] and guinea pigs [128,137,138,140] although Millan et al (2001) reported a 50% increase in firing rates following administration of GR205171 [114]. Chronic administration of an NK 1 antagonist (L-730735) did not alter the firing rate of LC neurons, however in guinea pigs it induced an increase in burst firing similar to that observed following chronic imipramine [140].…”

Section: Locus Coeruleusmentioning

confidence: 50%

“…Similar SP-induced excitation of LC neurons is observed in slice preparations from rat [135] and guinea pigs [136,137] as well as following local infusion into the LC of guinea pigs [138]. While SP is excitatory, the effect of NK 1 receptor antagonists on basal firing of LC neurons is controversial.…”

Section: Locus Coeruleusmentioning

confidence: 58%

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Do Substance P and the NK1 Receptor have a Role in Depression and Anxiety?

McLean¹

2005

CPD

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Research on Substance P (SP) has, until recently, focused on its role in pain and inflammation. However, a report that NK(1) receptor antagonists have utility in the treatment of depression has stimulated research into the function of SP and the NK(1)receptor in anxiety and depression. The distribution of SP and the NK(1) receptor in brain areas implicated in anxiety and depression is initially reviewed. This is followed by evaluation of the preclinical data obtained for SP and NK(1) receptor antagonists in behavioral models of depression as well as the phenotype of genetically modified animals lacking the genes encoding for the NK(1) receptor or for SP. The weight of the evidence supports antidepressant and anxiolytic activity of NK(1) receptor antagonists. However, many of the studies do not control for nonspecific effects of the compounds, and when enantiomers that lack activity at the NK(1) receptor are included, the results, in some cases, suggest that blockade of NK(1) receptors does not account for the observed behavioral activity. Finally, clinical studies in depressed patients assessing SP levels in plasma and cerebrospinal fluid as well as the effect of NK(1) receptor antagonists are reviewed. The clinical studies are a mixture of positive, failed and negative studies on the antidepressant activity of NK(1) receptor antagonists, not unlike the early clinical results obtained with selective serotonin reuptake inhibitors.

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Section: Locus Coeruleussupporting

confidence: 60%

Section: Locus Coeruleusmentioning

confidence: 50%

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Do Substance P and the NK1 Receptor have a Role in Depression and Anxiety?

McLean¹

2005

CPD

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“…SP (NK1R), glutamate and NO are known as pro-nociceptive and central pain mediators [30] in addition to producing anxiogenic responses [1,20,44]. SP via its NK1R participates to the initiation or the modulation of central behavioral responses to stress and pain stimuli [8][9][10]45]. Stimulation of the ionotropic glutamate NMDA receptor causes intraneuronal elevation of Ca 2+ which stimulates NOS, and the production of NO.…”

Section: Discussionmentioning

confidence: 99%

Brain kinin B1 receptor is upregulated by the oxidative stress and its activation leads to stereotypic nociceptive behavior in insulin-resistant rats

et al. 2015

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“…They recently reported on the pharmacological and biochemical characterisation of this compound, where it was reported to inhibit citric acid-induced cough in guinea-pigs [117,118].…”

Section: Competitive Environmentmentioning

confidence: 98%

Potential therapeutic targets for neurokinin-1 receptor antagonists

Duffy¹

2004

Expert Opinion on Emerging Drugs

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The peptide substance P and its tachykinin receptor, neurokinin-1 (NK1), have been the focus of considerable research for their role in a variety of both central and peripheral diseases. Recent preclinical data, as well as relevant clinical findings, support the potential therapeutic value of NK1 receptor antagonists in centrally mediated disease states, including anxiety and depression. In addition, a separate body of literature supports the use of NK1 receptor antagonists as inhibitors of centrally mediated emetic and cough responses. The role of NK1 receptor antagonists as analgesic agents with potential to treat migraine headache has also been investigated. NK1 receptors are also found in a number of peripheral regions, including the bladder, gastrointestinal tract and bone marrow. Preclinical models have been employed to address the potential therapeutic uses for NK1 receptor antagonists in diseases associated with inflammatory responses, including asthma, irritable bowel syndrome and cystitis of the bladder. Finally, other more recent publications suggest a role for NK1 receptor antagonists as tumour suppressants and haematopoietic agents. These applications for NK1 receptor antagonists are discussed in this review.

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SSR240600 [(R)-2-(1-{2-[4-{2-[3,5-Bis(trifluoromethyl)phenyl]acetyl}-2-(3,4-dichlorophenyl)-2-morpholinyl]ethyl}-4-piperidinyl)-2-methylpropanamide], a Centrally Active Nonpeptide Antagonist of the Tachykinin Neurokinin 1 Receptor: II. Neurochemical and Behavioral Characterization

Abstract: , a new nonpeptide tachykinin neurokinin 1 (NK 1 ) receptor antagonist, was evaluated against the neurochemical, electrophysiological, and behavioral effects provoked by direct activation of brain tachykinin NK 1 receptors or by stress in guinea pigs. SSR240600 (0

Cited by 37 publications

References 38 publications

Do Substance P and the NK1 Receptor have a Role in Depression and Anxiety?

Do Substance P and the NK1 Receptor have a Role in Depression and Anxiety?

Brain kinin B1 receptor is upregulated by the oxidative stress and its activation leads to stereotypic nociceptive behavior in insulin-resistant rats

Potential therapeutic targets for neurokinin-1 receptor antagonists

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