Is there still a future for neurokinin 3 receptor antagonists as potential drugs for the treatment of psychiatric diseases?

Beeské, Sandra

doi:10.1016/j.pharmthera.2011.09.007

Cited by 28 publications

(21 citation statements)

References 82 publications

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“…Numerous studies indicated that the function of NK3R related to tachykinins exert a plethora of biological effects, including smooth muscle contraction and relaxation, vasodilatation, secretion, activation of the immune system, pain transmission and neurogenic inflammation, and are implicated in a broad range of CNS disorders [27, 28]. Here, we described further evidence that NKB could function as an endogenous angiogenesis inhibitor.…”

Section: Discussionsupporting

confidence: 55%

Targeting neurokinin-3 receptor: a novel anti-angiogenesis strategy for cancer treatment

et al. 2017

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Angiogenesis is essential for tumor growth and metastasis, controlling angiogenesis is a promising strategy in cancer treatment. However, thus farther severe side effects of anti-angiogenic drugs have been rather demonstrated, stimulating interest in seeking novel targets of anti-angiogenesis. Neurokinin receptors, also known as tachykinin receptors, are usually considered as drug targets due to diverse physiological functions and their tractability. Although Neurokinin B, the selective natural agonist of neurokinin-3 receptor, have been shown to exhibit anti-angiogenesis activity, the effect and mechanism of neurokinin-3 receptor-mediated angiogenesis still remains unclear. In the present study, we demonstrated that [Mephe7]NKB, an analogue of NKB, possess significant anti-angiogenic effect on CAM. Furthermore, by introducing the tumor angiogenesis homing sequence (NGR), we designed and synthesized two novel agonist analogues of NK3R, NK3R-A1 and NK3R-A2. Both of the two analogues exhibit more efficient anti-migration effect on HUVECs by activating NK3R in vitro, and showed potent antitumor activities with no significant side effects in vivo. Taken together, our results illuminated that NK3R might be a potential novel target for the anti-angiogenesis therapy. Notably, NK3R-A1 might be used as a template for the development of the anti-tumor drugs on the basis of the anti-angiogenesis strategy.

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Section: Discussionsupporting

confidence: 55%

Targeting neurokinin-3 receptor: a novel anti-angiogenesis strategy for cancer treatment

et al. 2017

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“…However, late-stage clinical trials with NK 2 receptor blockers have shown either negative or inconclusive results in GAD, SAD and PTSD 81 . Thus, selective blockade of tachykinin receptors may be insufficient to achieve therapeutic efficacy 81,86 . Differences in tachykinin receptor physiology between rodents and humans have also been suggested to account for at least some of the failure to translate preclinical data on this target to the clinic 81 .…”

Section: Neuropeptidesmentioning

confidence: 99%

50 years of hurdles and hope in anxiolytic drug discovery

Griebel

Holmes

2013

Nat Rev Drug Discov

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358

346

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Anxiety disorders are the most prevalent group of psychiatric diseases, and have high personal and societal costs. The search for novel pharmacological treatments for these conditions is driven by the growing medical need to improve on the effectiveness and the side effect profile of existing drugs. A huge volume of data has been generated by anxiolytic drug discovery studies, which has led to the progression of numerous new molecules into clinical trials. However, the clinical outcome of these efforts has been disappointing, as promising results with novel agents in rodent studies have very rarely translated into effectiveness in humans. Here, we analyse the major trends from preclinical studies over the past 50 years conducted in the search for new drugs beyond those that target the prototypical anxiety-associated GABA (γ-aminobutyric acid)–benzodiazepine system, which have focused most intensively on the serotonin, neuropeptide, glutamate and endocannabinoid systems. We highlight various key issues that may have hampered progress in the field, and offer recommendations for how anxiolytic drug discovery can be more effective in the future.

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“…In the CNS, SP, NKB, and their receptors are highly expressed in regions of the brain that are important for cognition and emotion, 10,11 and antagonists for NK3-R are currently being pursued as therapeutics in a range of disorders including schizophrenia. 12,13 The tachykinins have a well-documented involvement in several neurodegenerative disorders, particularly Alzheimer's disease (AD); 2 for example, AD patients appear to have diminished SP expression, 14 and there is also evidence that NKB has a role. Studies have shown that both NKB and SP appear to be able to protect neurons against the toxic effects of Aβ peptides.…”

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confidence: 99%

The Tachykinin Peptide Neurokinin B Binds Copper Forming an Unusual [Cu^II(NKB)₂] Complex and Inhibits Copper Uptake into 1321N1 Astrocytoma Cells

Russino

McDonald

Hejazi

et al. 2013

ACS Chem. Neurosci.

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Neurokinin B (NKB) is a member of the tachykinin family of neuropeptides that have neuroinflammatory, neuroimmunological, and neuroprotective functions. In a neuroprotective role, tachykinins can help protect cells against the neurotoxic processes observed in Alzheimer's disease. A change in copper homeostasis is a clear feature of Alzheimer's disease, and the dysregulation may be a contributory factor in toxicity. Copper has recently been shown to interact with neurokinin A and neuropeptide γ and can lead to generation of reactive oxygen species and peptide degradation, which suggests that copper may have a place in tachykinin function and potentially misfunction. To explore this, we have utilized a range of spectroscopic techniques to show that NKB, but not substance P, can bind Cu II in an unusual [Cu II (NKB) 2 ] neutral complex that utilizes two N-terminal amine and two imidazole nitrogen ligands (from each molecule of NKB) and the binding substantially alters the structure of the peptide. Using 1321N1 astrocytoma cells, we show that copper can enter the cells and subsequently open plasma membrane calcium channels but when bound to neurokinin B copper ion uptake is inhibited. This data suggests a novel role for neurokinin B in protecting cells against copper-induced calcium changes and implicates the peptide in synaptic copper homeostasis. KEYWORDS: Neurokinin B, tachykinin, copper, calcium, neurodegeneration, substance P, Fura2, EPR N eurokinin B (NKB, neuromedin K) is a 10 residue peptide that belongs to the tachykinin family of neuropeptides. Other members include the mammalian peptides substance P (SP), neurokinin A (NKA), the Nterminally extended forms of NKA neuropeptide K and neuropeptide γ, and hemokinin.1 The family is characterized by the presence of a common C-terminal sequence FxGLM-NH 2 , which is thought to be important for receptor binding and activation.2 The biological activity of the tachykinin peptides lies with their ability to bind to G protein-coupled receptors and to mediate intracellular calcium release via several signaling pathways, including a G q/11 -coupled pathway, which involves the downstream generation of the second messengers diacylglycerol and IP 3 .2,3 SP, NKA, and NKB bind to neurokinin receptors NK1-R, NK2-R, and NK3-R, and although each peptide can bind to all the receptors, each has a preference for a particular receptor. Thus SP has a preference for NK1-R, NKA for NK2-R, and NKB for NK3-R. The structure of the peptides bound to their receptors is unclear; however, a recent modeling study looking at the interaction of NKB with NK3-R has highlighted not only how the C-terminal conserved domain directs receptor binding but also how the Nterminal residues may be involved in mediating receptor preference. 4 Functionally, the tachykinins are involved in a diverse range of cellular signaling processes including roles in neuroprotection, neuroinflammation, and neurotrophic pathways.

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Is there still a future for neurokinin 3 receptor antagonists as potential drugs for the treatment of psychiatric diseases?

Cited by 28 publications

References 82 publications

Targeting neurokinin-3 receptor: a novel anti-angiogenesis strategy for cancer treatment

Targeting neurokinin-3 receptor: a novel anti-angiogenesis strategy for cancer treatment

50 years of hurdles and hope in anxiolytic drug discovery

The Tachykinin Peptide Neurokinin B Binds Copper Forming an Unusual [Cu^II(NKB)₂] Complex and Inhibits Copper Uptake into 1321N1 Astrocytoma Cells

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Is there still a future for neurokinin 3 receptor antagonists as potential drugs for the treatment of psychiatric diseases?

Cited by 28 publications

References 82 publications

Targeting neurokinin-3 receptor: a novel anti-angiogenesis strategy for cancer treatment

Targeting neurokinin-3 receptor: a novel anti-angiogenesis strategy for cancer treatment

50 years of hurdles and hope in anxiolytic drug discovery

The Tachykinin Peptide Neurokinin B Binds Copper Forming an Unusual [CuII(NKB)2] Complex and Inhibits Copper Uptake into 1321N1 Astrocytoma Cells

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The Tachykinin Peptide Neurokinin B Binds Copper Forming an Unusual [Cu^II(NKB)₂] Complex and Inhibits Copper Uptake into 1321N1 Astrocytoma Cells