Identification, biological characterization and pharmacophoric analysis of a new potent and selective NK1 receptor antagonist clinical candidate

Fabio, Romano Di; Alvaro, Giuseppe; Braggio, Simone; Carletti, Renzo; Gerrard, Philip; Griffante, Cristiana; Marchioro, Carla; Pozzan, Alfonso; Melotto, Sergio; Poffe, Alessandro; Piccoli, Laura; Ratti, Emiliangelo; Tranquillini, Elvira; Trower, Michael K.; Spada, Simone; Corsi, Mauro

doi:10.1016/j.bmc.2013.09.001

Cited by 20 publications

(21 citation statements)

References 44 publications

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“…Many of these NK-1R antagonists have reached phase II and III clinical trials with one, aprepitant, currently approved by the United States Food and Drug Administration (Quartara and Altamura, 2006; Quartara et al, 2009; Di Fabio et al, 2013). The non-peptide NK-1R antagonist CP-96,345 has been reported to downregulate constitutive substance P mRNA expression in human mononuclear cells (Lai et al, 2002) and the ability of such NK-1R antagonists to treat a range of gastrointestinal, respiratory and urogenital, and sensory disorders has been explored.…”

Section: The Therapeutic Potential Of Nk-1r Antagonists In Inflammatomentioning

confidence: 99%

“…In addition to use as an anti-emetic, there has been promising research that aprepitant and other NK-1R antagonists may have efficacy against other CNS disorders including depression. The NK-1R antagonist MK-869 has been shown to effectively suppress depressive behavior in guinea pigs, and both MK-869 and casopitant successfully completed phase II clinical trials to treat depression (Kramer et al, 1998; Ebner and Singewald, 2006; Di Fabio et al, 2013). However, it must be noted that MK-869 failed in a phase III trial to treat major depressive disorder (Keller et al, 2006).…”

Section: The Therapeutic Potential Of Nk-1r Antagonists In Inflammatomentioning

confidence: 99%

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The Therapeutic Potential of Targeting Substance P/NK-1R Interactions in Inflammatory CNS Disorders

Johnson

Young

Marriott

2017

Front. Cell. Neurosci.

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The inflammatory responses of resident central nervous system (CNS) cells are now known to play a critical role in the initiation and progression of an array of infectious and sterile neuroinflammatory disorders such as meningitis, encephalitis, Parkinson’s disease, Alzheimer’s disease and multiple sclerosis (MS). Regulating glial inflammatory responses in a timely manner is therefore critical in preserving normal CNS functions. The neuropeptide substance P is produced at high levels within the CNS and its selective receptor, the neurokinin 1 receptor (NK-1R), is abundantly expressed by neurons and is present on glial cell types including microglia and astrocytes. In addition to its functions as a neurotransmitter in the perception of pain and its essential role in gut motility, this tachykinin is widely recognized to exacerbate inflammation at peripheral sites including the skin, gastrointestinal tract and the lungs. Recently, a number of studies have identified a role for substance P and NK-1R interactions in neuroinflammation and described the ability of this neuropeptide to alter the immune functions of activated microglia and astrocytes. In this review article, we describe the expression of substance P and its receptor by resident CNS cells, and we discuss the ability of this neuropeptide to exacerbate the inflammatory responses of glia and immune cells that are recruited to the brain during neurodegenerative diseases. In addition, we discuss the available data indicating that the NK-1R-mediated augmentation of such responses appears to be detrimental during microbial infection and some sterile neurodegenerative disorders, and propose the repurposed use of NK-1R antagonists, of a type that are currently approved as anti-emetic and anti-anxiolytic agents, as an adjunct therapy to ameliorate the inflammatory CNS damage in these conditions.

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Section: The Therapeutic Potential Of Nk-1r Antagonists In Inflammatomentioning

confidence: 99%

Section: The Therapeutic Potential Of Nk-1r Antagonists In Inflammatomentioning

confidence: 99%

The Therapeutic Potential of Targeting Substance P/NK-1R Interactions in Inflammatory CNS Disorders

Johnson

Young

Marriott

2017

Front. Cell. Neurosci.

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“…Given that the affinity of NK‐1 antagonists for mouse and rat NK‐1 receptors is often low , as opposed to the usual high affinity for those from other rodents and human , then this study was undertaken in the Mongolian gerbil that has also previously been shown to be a supportive model of humans for studying the central effects of NK‐1 antagonists . The high affinity of orvepitant for the gerbil NK‐1 receptor has been confirmed as pKi = 10.5 . In addition, to demonstrate that the scratching behaviour is being elicited by the NK‐1 receptor, then a potent and specific agonist for this receptor (GR73632) was used for the intra‐dermal injections to induce the scratching behaviour, rather than SP .…”

Section: Introductionmentioning

confidence: 97%

“…Orvepitant is a ‘novel generation’ centrally penetrant, selective and potent, small‐molecule non‐surmountable NK‐1 receptor antagonist that features high receptor occupancy and full and long lasting (≥24 h) central NK‐1 receptor occupancy . It has already demonstrated a positive antidepressant effect in a Phase II clinical study together with beneficial effects on sleep .…”

Section: Introductionmentioning

confidence: 99%

Neurokinin‐1 receptor antagonist orvepitant is an effective inhibitor of itch‐associated response in a Mongolian gerbil model of scratching behaviour

Trower

Fisher²,

Upton³

et al. 2014

Experimental Dermatology

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Data suggest that substance P could play an important role in pruritus, and therefore, blockade of the neurokinin (NK)-1 receptor might be antipruritic. Thus, we explored in the Mongolian gerbil the effect on scratching behaviour, induced by intra-dermal injection of the NK-1 receptor-specific agonist GR73632, of oral administration of the NK-1 receptor antagonist orvepitant. Orvepitant at all doses tested (0.1-10 mg/kg p.o.) produced a profound inhibition of GR73632 (30 nmol i.d.)induced hindlimb scratching; the minimum effective dose of orvepitant in this model was identified as ≤0.1 mg/kg. The data generated supported the proposition that the antipruritic potential of orvepitant should be evaluated in clinical trials.

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“…(44-46) For initial characterization studies, a short hydrophilic linker (to improve hydrophilicity) was introduced between L-733,060 and rhodamine to create an NK1R-targeted dye 5 that could be easily detected by confocal microscopy and flow cytometry (Scheme 1-3). …”

Section: Resultsmentioning

confidence: 99%

Design, Synthesis, and Evaluation of a Neurokinin-1 Receptor-Targeted Near-IR Dye for Fluorescence-Guided Surgery of Neuroendocrine Cancers

Kanduluru

Srinivasarao

2016

Bioconjugate Chem.

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The neurokinin-1 receptor (NK1R) is implicated in the growth and metastasis of many tumors, including cancers of the brain (e.g. gliomas, glioblastomas, astrocytomas), skin (e.g. melanomas), and neuroendocrine tissues (cancers of the breast, stomach, pancreas, larynx and colon). Because overexpression of NK1R has been reported in most of these malignancies, we have undertaken to design an NK1R-targeted near infrared (NIR) fluorescent dye for fluorescence guided surgeries of these cancers. We demonstrate here that an NK1R-binding ligand linked to the NIR dye LS288 selectively accumulates in NK1R-expressing tumor xenografts with high affinity (Kd = 13 nM), allowing intra-operative imaging of these cancers in live mice. Because tumor accumulation is nearly quantitatively blocked by excess unlabeled ligand, and since NK1R negative tumors and normal tissues display virtually no uptake, we conclude that the observed tumor retention is NK1R mediated. Results on the synthesis, in vitro characterization, and animal testing of NK1R-targeted NIR dye are presented.

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Identification, biological characterization and pharmacophoric analysis of a new potent and selective NK1 receptor antagonist clinical candidate

Cited by 20 publications

References 44 publications

The Therapeutic Potential of Targeting Substance P/NK-1R Interactions in Inflammatory CNS Disorders

The Therapeutic Potential of Targeting Substance P/NK-1R Interactions in Inflammatory CNS Disorders

Neurokinin‐1 receptor antagonist orvepitant is an effective inhibitor of itch‐associated response in a Mongolian gerbil model of scratching behaviour

Design, Synthesis, and Evaluation of a Neurokinin-1 Receptor-Targeted Near-IR Dye for Fluorescence-Guided Surgery of Neuroendocrine Cancers

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