Substance P receptor antagonists in psychiatry: Rationale for development and therapeutic potential

Department of Psychiatry and Psychotherapy, University of Freiburg Medical School, Freiburg, Germany.
CNS Drugs (Impact Factor: 4.38). 02/2005; 19(4):275-93.
Source: PubMed

ABSTRACT Increasing evidence suggests that substance P (SP) and its receptor (neurokinin [NK]-1 receptor [NK1R]) might play an important role in the modulation of stress-related, affective and/or anxious behaviour. First, SP and NK1R are expressed in brain regions that are involved in stress, fear and affective response (e.g. amygdala, hippocampus, hypothalamus and frontal cortex). Second, the SP content in these areas changes upon application of stressful stimuli. Third, the central administration of SP produces a range of fear-related behaviours. In addition, the SP/NK1R system shows significant spatial overlap with neurotransmitters such as serotonin and noradrenaline (norepinephrine), which are known to be involved in the regulation of stress, mood and anxiety. Therefore, it was hypothesised that blockade of the NK1R might have anxiolytic as well as antidepressant effects. Preclinical studies investigating the effects of genetic or pharmacological NK1R inactivation on animal behaviour in assays relevant to depression and anxiety revealed that the behavioural changes resemble those seen with reference antidepressant or anxiolytic drugs. Furthermore, antagonism or genetic inactivation of the NK1R causes alterations in serotonin and norepinephrine neuronal transmission that are likely to contribute to the antidepressant/anxiolytic activity of NK1R antagonists but that are--at least partially--distinct from those produced by established antidepressant drugs. This underlines the conceivable unique mechanism of action of this new class of compounds. In three independent clinical trials with three different compounds (aprepitant [MK-869], L-759274 and CP-122721), an antidepressant effect of NK1R antagonists could be demonstrated. These results, however, have been challenged by recent failed studies with aprepitant. There are numerous indications from preclinical studies that, in addition to SP and NK1R, other neurokinins and/or neurokinin receptors might also be involved in the modulation of stress-related behaviour and that exclusive blockade of the NK1R might not be sufficient to produce consistent anxiolytic and antidepressant effects. One such candidate is the neurokinin-2 receptor (NK2R), and clinical trials to assess the antidepressant effects of NK2R antagonists are currently underway. Of special interest might also be substances that block more than one receptor type such as NK1/2R antagonists or NK1/2/3R antagonists. These compounds may be more efficacious in antagonising the effects of SP than compounds that only block the NK1R.

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    • "Neurokinin (NK)1 receptors as target for anxiety disorders (Ebner et al., 2009; Griebel and Holmes, 2013; Herpfer and Lieb, 2005; Kwako et al., 2015; Mathew et al., 2011; Tauscher et al., 2010). "
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    ABSTRACT: Psychopharmacology has had some bad publicity lately. Frankly, there have been some major problems along the way in developing new effective drugs for psychiatric disorders. After a prolonged period of high investments but low success rates, big pharmaceutical companies seem to retract their activities in the psychopharmacology field. Yet, the burden of mental disorders is likely to keep on growing in the next decades. In this position paper, we focus on drug development for depression and anxiety disorders, to narrow the scope of the assay. We describe the current situation of the psychopharmacology field, and analyse some of the methods and paradigms that have brought us here, but which should perhaps change to bring us even further. In addition, some of the factors contributing to the current stagnation in psychopharmacology are discussed. Finally, we suggest a number of changes that could lead to a more rational strategy for central nervous system drug development and which may circumvent some of the pitfalls leading to "me too" approaches. Central to the suggested changes, is the notion that mental disorders do not lead to several symptoms, but a network of causally related symptoms convolutes into a mental disorder. We call upon academia to put these changes in the early phases of drug development into effect. Copyright © 2015. Published by Elsevier B.V.
    European journal of pharmacology 03/2015; 759. DOI:10.1016/j.ejphar.2015.03.020 · 2.68 Impact Factor
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    • "Isolation-induced emotional stress and acute stress of foot shock both result in higher levels of SP in specific brain tissues (Mello et al., 2007; Ebner and Singewald, 2006; Hasen√∂hrl et al., 2000). In addition, the central administration of SP produces a range of fear-related behavior in rats (Herpfer and Lieb, 2005). In cerebrospinal fluid of the patients with depression, SP levels are significantly higher compared to healthy people (Geracioti et al., 2006). "
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    ABSTRACT: Substance P (SP) levels are closely related with the pathogenesis of depression. Recent work has focused on the antidepressive effect of substance P receptor antagonist (SPA), however, its action site and mechanism remain largely unresolved. Our previous results showed that the lateral habenula (LHb) plays a key role in the pathogenesis of depression. The current study investigates the effects of SPA microinjected into the LHb on the behavioral responses of two types of rats that exhibit depression-like behavior. To produce adult rats that exhibit depression-like behavior, rats were either exposed to chronic mild stress (CMS), or clomipramine (CLI), a tricyclic antidepressant, was chronically administered to the rats during the neonatal state of life. The forced-swimming test (FST) was used to evaluate the behavioral responses of the rats. Furthermore, we measured serotonin (5-HT) levels in the dorsal raphe nucleus (DRN) using microdialysis. The FST showed that the immobility time decreased and the climbing time increased after SPA injection into the LHb of depression-like behavior rats. In addition, the 5-HT levels in the DRN increased after SPA was microinjected into the LHb of rats that exhibited depression-like behavior. This study demonstrates that the LHb mediates the antidepressive effect of SPA by increasing the 5-HT levels in the DRN, suggesting that the LHb may be a potential target of antidepressant.
    Brain research bulletin 10/2013; 100. DOI:10.1016/j.brainresbull.2013.10.007 · 2.97 Impact Factor
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    • "The initial interest in this neuropeptide and receptor family for mood and anxiety conditions reflected its extensive colocalization with monoamine neurotransmitters (Ebner et al, 2004) and abundant expression in stress neural circuitry. Genetic or pharmacologic blockade of NK-1 receptors were observed to induce many of the same long-term neural effects as standard antidepressants on cell signaling molecules such as BDNF and hippocampal neurogenesis (Blier et al, 2004; van der Hart et al, 2005), providing the rationale for experimental therapeutic trials in mood and anxiety disorders (Herpfer and Lieb, 2005). Despite the promising preclinical data, a recent pooled analysis of five 8-week randomized, doubleblind , placebo-controlled, multicenter studies of the NK-1 receptor antagonist aprepitant in over 2500 patients with major depression failed to demonstrate efficacy (Keller et al, 2006). "
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    ABSTRACT: Monoaminergic-based drugs remain the primary focus of pharmaceutical industry drug discovery efforts for mood disorders, despite serious limitations regarding their ability to achieve remission. The quest for novel therapies for unipolar depression and bipolar disorder has generally centered on two complementary approaches: (1) understanding the presumed therapeutically relevant biochemical targets of currently available medications, and using that knowledge to design new drugs directed at both direct biochemical targets and downstream targets that are regulated by chronic drug administration; and (2) developing pathophysiological models of the illness to design therapeutics to attenuate or prevent those pathological processes. This review describes several promising drugs and drug targets for mood disorders using one or both of these approaches. Agents interacting with non-catecholamine neurotransmitter systems with particular promise for unipolar and bipolar depression include excitatory amino acid neurotransmitter modulators (eg, riluzole, N-methyl-D-aspartate antagonists, and AMPA receptor potentiators) and neuropeptide antagonists (targeting corticotropin releasing factor-1 and neurokinin receptors). Potential antidepressant and mood-stabilizing agents targeting common intracellular pathways of known monoaminergic agents and lithium/mood stabilizers are also reviewed, such as neurotrophic factors, extracellular receptor-coupled kinase (ERK) mitogen-activated protein (MAP) kinase and the bcl-2 family of proteins, and inhibitors of phosphodiesterase, glycogen synthase kinase-3, and protein kinase C. A major thrust of drug discovery in mood disorders will continue efforts to identify agents with rapid and sustained onsets of action (such as intravenous administration of ketamine), as well as identify drugs used routinely in non-psychiatric diseases for their antidepressant and mood-stabilizing properties.
    Neuropsychopharmacology 09/2008; 33(9):2300. DOI:10.1038/npp.2008.84 · 7.83 Impact Factor
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