Disease relevance of 1-[(3R)-3-(3,4-dichlorophenyl)-3-[2-(4-phenyl-1-azoniabicyclo[2.2.2]oct-1-yl)ethyl]-1-piperidyl]-2-(3-isopropoxyphenyl)ethanone

• Univariate analysis revealed increased radiation injury score, bowel wall thickening, and collagen III deposition after treatment with CGRP(8-37), whereas SR140333 ameliorated radiation injury score, loss of mucosal surface area, collagen III deposition, and mucosal inflammation [1].
• The NK(1) receptor antagonists, SDZ NKT 343, RPR100893 and SR140333, reduced mechanical hyperalgesia by 68, 36 and 27% at a dose of 30 mg kg(-1) p.o., respectively [2].
• NGF-induced edema was not reduced by the neurokinin-1 receptor antagonist SR140333, but attenuated by the CGRP receptor antagonist CGRP[8-37] [3].
• Both stress-induced visceral hypersensitivity in intact rats and the hormonally-restored visceral hyper-responsiveness of OVX rats were antagonized by SR140333 [4].
• Human colonic anti-secretory activity of the potent NK(1) antagonist, SR140333: assessment of potential anti-diarrhoeal activity in food allergy and inflammatory bowel disease [5].

Psychiatry related information on 1-[(3R)-3-(3,4-dichlorophenyl)-3-[2-(4-phenyl-1-azoniabicyclo[2.2.2]oct-1-yl)ethyl]-1-piperidyl]-2-(3-isopropoxyphenyl)ethanone

• The same doses of SR140333 given post-trial had minor facilitative effects on inhibitory avoidance learning and open-field habituation, but did not have reinforcing effects in a conditioned place preference (CPP) task [6].

High impact information on 1-[(3R)-3-(3,4-dichlorophenyl)-3-[2-(4-phenyl-1-azoniabicyclo[2.2.2]oct-1-yl)ethyl]-1-piperidyl]-2-(3-isopropoxyphenyl)ethanone

• The selective rNK1 antagonist SR140333 totally reversed the effect of SP on progesterone conversion into 5alpha-DHP and 3alpha,5alpha-THP [7].
• This elevated plasma leak was attenuated by recombinant NEP or the NK1R antagonist SR140333, and is thus caused by diminished degradation of SP [8].
• The exacerbated inflammation in knockout mice was prevented by recombinant NEP and SR140333 [8].
• The carrageenin (500 microg)-induced response was inhibited (p < 0.05) by a NK1 receptor antagonist, SR140333 (480 nmol/kg i.v. at -5 min), in the wild-type group [9].
• Histamine release was measured from colonic samples of control and stressed animals and the effect of SR140333, a NK1 receptor antagonist, on substance P induced histamine release was determined [10].

Biological context of 1-[(3R)-3-(3,4-dichlorophenyl)-3-[2-(4-phenyl-1-azoniabicyclo[2.2.2]oct-1-yl)ethyl]-1-piperidyl]-2-(3-isopropoxyphenyl)ethanone

• SR140333 had no significant effect on either the EAR or the LAR compared with saline control inhalations [11].
• Treatment with SR140333 (0.5 mg kg(-1)) significantly reversed severe reperfusion-induced local and remote increases in vascular permeability, neutrophil recruitment, intestinal haemorrhage and blood neutropaenia, but did not prevent the lethality associated with severe I/R [12].
• In alphaCGRP knockout mice, mustard oil also caused plasma extravasation and vasodilatation, which were both inhibited by treatment with SR140333 [13].
• SP-induced NK1 receptor endocytosis was inhibited by the specific NK1 receptor antagonist, SR140333 [14].
• Treatment of rats with SR140333 had no influence on the long-term downregulation of TRPV1 mRNA by capsaicin [15].

Anatomical context of 1-[(3R)-3-(3,4-dichlorophenyl)-3-[2-(4-phenyl-1-azoniabicyclo[2.2.2]oct-1-yl)ethyl]-1-piperidyl]-2-(3-isopropoxyphenyl)ethanone

• Dilatations were reduced slightly by ganglionic application of NK1 and NK3 receptor antagonists (SR140333, SR142801; 1 microM), but were reduced significantly by bathing the ganglia in 0.5 mM Ca2+ and 10 mM Mg2+ [16].
• Similarly, SR140333 failed to affect the bone marrow eosinophilia observed at 48 h after antigen challenge of immunized mice [17].
• Since SR140333 reduced the secretory response to mast cell and afferent stimulation this compound may be particularly useful in reducing the symptoms of food allergy [5].
• Pretreatment with SR140333 failed to prevent the antigen-induced increase of interleukin-5 concentrations in the pleural cavity [17].
• Neurokinin-1 receptor antagonism by SR140333: enhanced in vivo ACh in the hippocampus and promnestic post-trial effects [6].

Associations of 1-[(3R)-3-(3,4-dichlorophenyl)-3-[2-(4-phenyl-1-azoniabicyclo[2.2.2]oct-1-yl)ethyl]-1-piperidyl]-2-(3-isopropoxyphenyl)ethanone with other chemical compounds

• EXPERIMENTAL DESIGN: Male rats received full-length CGRP, CGRP antagonist (CGRP(8-37)), a modified substance P peptide (GR73632), a small-molecule substance P receptor antagonist (neurokinin-1 receptor antagonist, SR140333), or vehicle for 2 weeks after localized X irradiation of a 4-cm loop of small bowel [1].
• Therefore, in a guinea pig model of allergic asthma, we investigated the involvement of the NK1 receptor in allergen-induced early (EAR) and late (LAR) asthmatic reactions, airway hyperreactivity (AHR) after these reactions and airway inflammation, using the selective nonpeptide NK1 receptor antagonist SR140333 [11].
• The NGF increase was suppressed by treatment of rats with the selective tachykinin NK1 receptor antagonist SR140333 (0.1 mg/kg), and by the beta adrenergic agonist terbutaline (0.3 mg/kg) [18].
• (4) The contractile responses to PAR-1 and PAR-2 activation were concentration-dependently attenuated by SR140333 (0.1-1 micro M), NK(1) receptor antagonist, or by SR48968 (0.1-1 micro M), NK(2) receptor antagonist [19].
• Capsaicin 0.5%, which stimulates release of endogenous substance P from sensory nerves, was also found to enhance synovial angiogenesis, [PCNA index 17% (95% CI, 14% to 19%)] compared with saline injected control knees [2% (95% CI, 1% to 3%), p < 0.05], and this also was inhibited by 1 micro mol of SR140333 [11% (95% CI, 8 to 16%)] [20].

Gene context of 1-[(3R)-3-(3,4-dichlorophenyl)-3-[2-(4-phenyl-1-azoniabicyclo[2.2.2]oct-1-yl)ethyl]-1-piperidyl]-2-(3-isopropoxyphenyl)ethanone

• The present studies used mdr1a-/- mice, a spontaneously occurring mutant that is deficient in P-gp, to examine the CNS penetration of SR140333 and GR205171 [21].
• The contractile effect of ET-1 was not affected by tetrodotoxin (1 microM), atropine (1 microM), methysergide (100 nM), chloropyramine (100 nM) or SR140333 (100 nM) but was significantly inhibited or even abolished by the receptor antagonist BQ123 (3 microM) or BQ788 (3 microM) [22].
• SR140333 less markedly attenuated the capsaicin-induced increase in phosphorylated STAT3: whereas in the sciatic nerve the difference was significant when the data at 3 h and 6 h were combined (p < 0.05), no such treatment effect of SR140333 was observed in the DRG [15].
• The NK1 receptor antagonist SR140333 inhibits capsaicin-induced ERK phosphorylation in sensory neurons [15].
• Cold-storage denervation, tetrodotoxin-TTX (1 mM), spantide (100 mM) and NK1-3 receptor antagonists SR140333, 48968, 142801 (up to 10 mM) notably diminished M15, galanin(1-14)-[Abu8]Scy-I, SP(5-11) and [Abu8]-Scy-I evoked contractions without affecting activities of galanin and galanin(1-15)-NH2 [23].

Analytical, diagnostic and therapeutic context of 1-[(3R)-3-(3,4-dichlorophenyl)-3-[2-(4-phenyl-1-azoniabicyclo[2.2.2]oct-1-yl)ethyl]-1-piperidyl]-2-(3-isopropoxyphenyl)ethanone

• We tested intraperitoneal or intrathecal injection of the NK(1)R antagonist SR140333 on the visceromotor reflex to colorectal distention in both groups at day 11 [24].
• On two different occasions, separated by 1 wk interval, OA-sensitized guinea pigs inhaled either saline (3 min) or SR140333 (100 nM, 3 min) at 30 min before as well as at 5.5 h after OA provocation (between the EAR and LAR) in a random crossover design [11].
• No further reduction was noted at higher doses (maximum 100 mg kg(-1) p.o.). The anti-hyperalgesic effect of SDZ NKT 343 and RPR100893 peaked at 3 h while SR140333 produced maximal reversal at 1 h after oral administration [2].
• We measured the effects of a selective non-peptide NK-1 receptor antagonist, SR140333 (1, 3 and 9 mg/kg i.p.) on ACh levels in frontal cortex, amygdala and hippocampus by microdialysis and HPLC [6].
• The latter was inhibited by the NK-1 receptor antagonist SR140333, showing the direct involvement of substance P and its receptor in this co-culture system [25].

References