Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Substance P (SP) belongs to the neurokinin (NK) family of neuropeptides and exerts its biological effects via interaction with the NK1 receptor. The SP-NK1 receptor system is one of the best-characterized neurotransmitter pathways in both the central and peripheral nervous systems. It has been postulated that this pathway may have important roles in a variety of centrally regulated pathophysiologic conditions, including depression. In animal models, central injection of SP was associated with a series of anxiety-like behaviors, and this response could be abolished by pretreatment with SP (NK1) receptor antagonists (SPAs). On the basis of these and other encouraging preclinical results, several clinical trials have examined the potential of SPAs in the treatment of depression. In phase 2 trials, therapy with the SPAs aprepitant (MK-0869) and compound A resulted in improvements in depression and anxiety symptoms that were quantitatively comparable with those seen with selective serotonin reuptake inhibitors (SSRIs) and significantly greater than those seen with placebo. These positive results have established a proof of concept that the inhibition of the SP-NK1 receptor pathway may be a potentially useful novel treatment option for management of patients with depression. The apparent lack of benefit with SPAs versus placebo in subsequent dose-finding studies with aprepitant and compound A is not surprising, considering the fact that the outcomes with an active control (SSRI) in these trials were also similar to those observed with placebo. Future trials with SPAs will focus on the identification of appropriate patients and drug regimens and will also define the role of these agents in the treatment of depression.
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PMID:Clinical experience with substance P receptor (NK1) antagonists in depression. 1256 40

The study of tachykinin NK1 (substance P) receptor antagonists has emerged as a field of great promise due to accumulating evidence that NK1 antagonists offer possible new treatment options in therapeutic areas ranging from pain, emesis, and pulmonary disorders to depression and anxiety. It is hoped that the unique mechanism of action of these agents, which involves modulation of effects mediated by the interaction of the neuropeptide substance P with it's G-protein coupled receptor, will provide improvements over existing therapies. For this reason many pharmaceutical companies are engaged in intense research programs with the goal of bringing safe and effective new drugs to the market. To date a wealth of diverse NK1 antagonists have been discovered, several of which have been evaluated in clinical trials. Despite rich structural diversity in this area of medicinal chemistry a number of structural features are commonly shared amongst otherwise unrelated antagonists. This theme and others are covered with the aim of conveying recent successful approaches to the discovery of potent and selective nonpeptide NK1 antagonists. This review focuses mainly on reports appearing in the year 2001 and the first half of 2002.
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PMID:Medicinal chemistry of selective neurokinin-1 antagonists. 1287 Nov 73

Neurokinin receptors in the central nervous system are involved in the neural circuitry of anxiety, depression and emesis. This has led to the development of nonpeptidic NK1 receptor antagonists as therapeutic agents. Clinical trials have shown that NK1 receptor antagonists have efficacy in chemotherapy-induced emesis and depression. Sequence polymorphisms can potentially influence the efficacy of drugs in patient populations and are an important consideration in the drug development process. To identify DNA sequence variants in the NK1 receptor, comparative DNA sequencing was performed on a population of 93 individuals. In total, 19 single-nucleotide polymorphisms (SNPs) were identified with one SNP (g.78351T>C) resulting in a tyrosine to histidine substitution at residue 192 (Y192H). The Y192H variant was expressed using site-directed mutagenesis and was characterized with respect to affinity, receptor kinetics, functional calcium response and receptor internalization. In all cases the Y192H variant was found to display properties similar to those of the wild-type receptor.
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PMID:Identification of single-nucleotide polymorphisms of the human neurokinin 1 receptor gene and pharmacological characterization of a Y192H variant. 1545 52

Although a wide assortment of agents is currently available for the treatment of depression, this disorder remains poorly managed in a large proportion of patients. Traditional antidepressant treatments target the biogenic amine systems. However, a growing body of evidence is implicating the involvement of neuropeptides in depression, especially the neurokinin substance P. This study evaluated the effects of selective antagonists of the tachykinin NK1, NK2, and NK3 receptors in the forced swim test, a commonly used screen for antidepressants. Rats were given CP-96,345 (2S, 3S)-cis-2-(diphenylmethyl)-N-[(2-methoxyphenyl)-methyl]-1-azabicyclo[2.2.2]octan-3-amine, SR 48968 (S)-N-methyl-N[4-(4-acetylamino-4-phenylpiperidino)-2-(3,4-dichlorophenyl)-butyl]benzamide, or SR 142801 (S)-(N)-(1-(3-(1-benzoyl-3-(3,4-dichlorophenyl) piperidin-3-yl) propyl)-4-phenylpiperidin-4-yl)-N-methylacetamide, antagonists of the NK1, NK2, and NK3 receptors, respectively, at doses of 2.5, 5, and 10 mg/kg, intraperitoneally (i.p.). The time of immobility during the forced swim test was used as an indicator of antidepressant activity of the antagonists. All antagonists decreased immobility times. CP-96,345 and SR 142801 showed dose-related effects; SR 48968 had its maximum effect at 2.5 mg/kg. The magnitude of the effects of the neurokinin receptor antagonists was approximately the same as that of amitriptyline and desipramine, two traditional antidepressants, both given at 10 mg/kg, i.p. This study provides comparative data on the relative effectiveness of NK1, NK2, and NK3 receptor antagonists in this screen for antidepressant drug activity.
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PMID:Antidepressant-like effects of neurokinin receptor antagonists in the forced swim test in the rat. 1565 99

Neurokinins (NK) are peptide molecules with modulatory actions on other neurotransmitter systems, notably the monoaminergic ones, within the central nervous system and peripheral tissues. A great deal of evidence supports a role for these substances, mainly for substance P and its main receptor NK1, in a number of physiologic and pathologic conditions, including affective and behavioral responses to stress. NK1 receptor antagonists have shown preclinical activity in several paradigms of anxiety and depression. Mutant mice lacking the NK1 receptor gene have an increased firing rate of dorsal raphe serotonergic neurons, an effect that can also be seen after the administration of substance P antagonists. When given chronically, NK1 antagonists promote an enhancement of serotonergic transmission in the hippocampus that seems to be mediated by interaction with other neurotransmission systems. Clinical efficacy of such drugs has also been demonstrated among patients with major depression, although the results have been inconclusive. More research is needed to elucidate the precise role these drugs could play in the treatment of affective disorders in the future.
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PMID:[The modulatory role of neurokinins in affective behaviors]. 1570 32

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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PMID:Substance P receptor antagonists in psychiatry: rationale for development and therapeutic potential. 1581 42

The main hypothesis regarding the mechanism of action of antidepressant drugs is monoaminergic and mainly involves two neurotransmitters, serotonin and noradrenaline. Despite the well-recognized therapeutic efficacy of selective serotonin reuptake inhibitors (SSRIs), some disadvantages still occur. For example, they often require 4-6 weeks to achieve clinical benefits in depressed patients. In the past, some molecules that could shorten this long delay of action have been identified. The role of presynaptic autoreceptors - the activation of which leads to an inhibitory feedback control on neurotransmitter synthesis and release - has been extensively studied for antidepressant effects. In our laboratory, we studied the combined effects of an SSRI and a serotonin autoreceptor antagonist of the 5-HT1B subtype using intracerebral in vivo microdialysis in awake, freely moving mice. Important information on SSRIs has been obtained by applying this technique to genetically modified animals, such as constitutive knockout (KO) mice lacking 5-HT1B receptors (5-HT1B KO) generated by homologous recombination: we compared the effects of a combined treatment on extracellular/intrasynaptic levels of serotonin in various nerve terminals area in wild-type control and KO mice. Thus, we found that indirect activation of 5-HT1B autoreceptors limits the effects of SSRIs on dialysate 5-HT levels at serotonergic nerve terminals such as the ventral hippocampus. The study of substance P (neurokinin 1 receptor [R-NK1]) offers another example of the use of KO mice in the development of a new class of antidepressant drugs. NK1 receptor antagonists may display anxiolytic/antidepressant-like properties. The lack of selective compounds for each tachykinin receptor subtype (R-NK 1, R-NK2 or R-NK3) and differences in their affinity between animal species have made R-NK1 KO mice a very useful experimental tool. In collaborative work we found that genetic (R-NK1 KO mice) or pharmacological (GR205171) blockade of R-NK1 is associated with several changes: the increase in cortical 5-HT outflow caused by systemic injection of paroxetine was 4- to 6-fold higher in freely moving R-NK1 KO mice than in wild-type controls. The constitutive lack of NK1 receptors is associated with a functional desensitization of somatodendritic 5-HT1A autoreceptors, resembling that induced by chronic treatment with SSRI antidepressants. These results highlight the link between a neurotransmitter (serotonin) and a neuropeptide (substance P). This genetic strategy allowed us to point out that multiple targets participate to the effects of classical antidepressant drugs within the brain. We hope that, soon, some mice lines (constitutive or tissue specific, conditional rescue mice having alterations of sleep/wakefulness and/or food intake, altered central serotonin and/or noradrenaline neurotransmission, deficit in neurotrophic factors, but increases in intrasynaptic concentrations of substance P) could be a relevant model of the physiopathology of depressive disorders, and could help us understand the appearance of some symptoms. These recent findings suggest that instead of being rejected, the monoaminergic hypothesis of depression should be improved, corrected and completed by studying the role of other neurotransmitter, neuromodulatory compounds (substance P, BDNF [brain-derived neurotrophic factor]). By doing so, it thus could be possible to improve antidepressant drug treatment, i.e. shorten their long delay of action and/or to decrease treatment resistance or improve its tolerance.
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PMID:[Mechanism of action of antidepressant drugs: importance of genetically modified mice in the pharmacological in vivo approach]. 1643 12

Local inhibition within the spinal cord dorsal horn is mediated by the neurotransmitters GABA and glycine and strongly influences nociceptive and temperature signaling. Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors are expressed by inhibitory interneurons and have been shown to modulate GABA release in other regions of the CNS. In the spinal cord, there is morphological evidence for presynaptic AMPA receptor subunits in GABAergic dorsal horn neurons, but functional data are lacking. To determine if AMPA receptors are indeed functional at presynaptic terminals of inhibitory neurons, we recorded evoked and miniature inhibitory postsynaptic currents (mIPSPs) in the superficial dorsal horn of the rat spinal cord. We show that AMPA receptor activation enhances spontaneous release of inhibitory amino acids in the presence of tetrodotoxin onto both lamina II neurons and NK1 receptor-expressing (NK1R+) lamina I neurons. This effect is sensitive to the concentration of extracellular Ca2+, yet is not fully blocked in most neurons in the presence of Cd2+, suggesting possible Ca2+ entry through AMPA receptors. Postsynaptic Ca2+ elevation is not required for these changes. AMPA-induced increases in mIPSP frequency are also seen in more mature dorsal horn neurons, indicating that these receptors may play a role in nociceptive processing in the adult. In addition, we have observed AMPA-induced depression of evoked release of GABA and glycine onto lamina I NK1R+ neurons. Taken together these data support a role for presynaptic AMPA receptors in modulating release of GABA and glycine in the superficial dorsal horn. Because inhibition in the dorsal horn is important for controlling pain signaling, presynaptic AMPA receptors acting to modulate the inhibitory inputs onto dorsal horn neurons would be expected to impact upon pain signaling in the spinal cord dorsal horn.
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PMID:Presynaptic alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors modulate release of inhibitory amino acids in rat spinal cord dorsal horn. 1647 27

Tachykinins play an important role as peptide modulators in the CNS. Based on the concentration and distribution of the peptides and their receptors, substance P (SP) and its cognate receptor neurokinin 1 (NK1R) seem to play a particularly important role in higher brain functions. They are expressed at high levels in the limbic system, which is the neural basis of emotional responses. Three different lines of evidence from physiological studies support such a role of SP in the regulation of emotionality: (1) stress is often associated with elevated level of SP in animals and humans; (2) systematic and local injections of SP influence anxiety levels in a dose-dependent and site-specific manner; (3) NK1 receptor antagonists show anxiolytic effects in different animal models of anxiety. Although these studies point to the NK1 receptor as a promising target for the pharmacotherapy of anxiety disorders, high affinity antagonists for the human receptors could not be studied in rats or mice due to species differences in the antagonist binding sites. However, studies on anxiety and depression-related behaviors have now been performed in mouse mutants deficient in NK1 receptor or SP and NKA. These genetic studies have shown that anxiety and depression-related phenotypes are profoundly affected by the tachykinin system. For example, NK1R-deficient mice seem to be less prone depression-related behaviors in models of depression, and one study also provided evidence for reduced anxiety levels. Mice deficient in SP and NKA behaved similarly as the NK1R knockouts. In animal models of anxiety they performed like wildtype mice treated with anxiolytic drugs. In behavioral paradigms related to depression they behaved like wildtype animals treated with antidepressants. In summary, the genetic studies clearly show that the SP/NK1 system plays an important role in the modulation of emotional behaviors.
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PMID:Mutagenesis and knockout models: NK1 and substance P. 1659 57

There is a growing interest in the potential anxiolytic- and antidepressant-like effects of compounds that target neurokinin receptors. Since the structure and the pharmacology of the human neurokinin receptor resembles that of gerbils, rather than that of mice or rats, we decided to investigate the anxiolytic- and /or antidepressant-like effects of NK1 (SSR240600), NK2 (saredutant) and NK3 (osanetant) receptor antagonists in gerbils. It was found that saredutant (3-10 mg/kg, p.o.) and osanetant (3-10 mg/kg, p.o.) produced anxiolytic-like effects in the gerbil social interaction test. These effects were similar to those obtained with the V1b receptor antagonist SSR149415 (3-10 mg/kg, p.o.), diazepam (1 mg/kg, p.o.) and buspirone (10 mg/kg, p.o.). Fluoxetine and SSR240600 were devoid of effects in this test. In the tonic immobility test in gerbils, saredutant (5-10 mg/kg, i.p.) and osanetant (5-10 mg/kg, i.p.) produced similar effects to those observed with fluoxetine (7.5-15 mg/kg, i.p.), SSR149415 (10-30 mg/kg, p.o.) and buspirone (3 mg/kg, i.p.). Diazepam and SSR240600 were inactive in this paradigm. In conclusion, the present study indicates further that NK2 and NK3 receptor antagonists may have therapeutic potential in the clinical management of anxiety and depression.
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PMID:Selective blockade of NK2 or NK3 receptors produces anxiolytic- and antidepressant-like effects in gerbils. 1662 95


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