Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0042963 (vomiting)
 31,883 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Structural modifications requiring novel synthetic chemistry were made to the morpholine acetal human neurokinin-1 (hNK-1) receptor antagonist 4, and this resulted in the discovery of 2-(R)-(1-(R)-3, 5-bis(trifluoromethyl)phenylethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-ox o-1 ,2,4-triazol-5-yl)methyl morpholine (17). This modified compound is a potent, long-acting hNK-1 receptor antagonist as evidenced by its ability to displace [125I]Substance P from hNK-1 receptors stably expressed in CHO cells (IC50 = 0.09 +/- 0.06 nM) and by the measurement of the rates of association (k1 = 2.8 +/- 1.1 x 10(8) M-1 min-1) and dissociation (k-1 = 0.0054 +/- 0.003 min-1) of 17 from hNK-1 expressed in Sf9 membranes which yields Kd = 19 +/- 12 pM and a t1/2 for receptor occupancy equal to 154 +/- 75 min. Inflammation in the guinea pig induced by a resiniferatoxin challenge (with NK-1 receptor activation mediating the subsequent increase in vascular permeability) is inhibited in a dose-dependent manner by the oral preadmininstration of 17 (IC50 (1 h) = 0.008 mg/kg; IC90 (24 h) = 1.8 mg/kg), indicating that this compound has good oral bioavailbility and peripheral duration of action. Central hNK-1 receptor stimulation is also inhibited by the systemic preadministration of 17 as shown by its ability to block an NK-1 agonist-induced foot tapping response in gerbils (IC50 (4 h) = 0.04 +/- 0.006 mg/kg; IC50 (24 h) = 0.33 +/- 0.017 mg/kg) and by its antiemetic actions in the ferret against cisplatin challenge. The activity of 17 at extended time points in these preclinical animal models sets it apart from earlier morpholine antagonists (such as 4), and the piperidine antagonists 2 and 3 and could prove to be an advantage in the treatment of chronic disorders related to the actions of Substance P. In part on the basis of these data, 17 has been identified as a potential clinical candidate for the treatment of peripheral pain, migraine, chemotherapy-induced emesis, and various psychiatric disorders.
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PMID:Structural optimization affording 2-(R)-(1-(R)-3, 5-bis(trifluoromethyl)phenylethoxy)-3-(S)-(4-fluoro)phenyl-4- (3-oxo-1,2,4-triazol-5-yl)methylmorpholine, a potent, orally active, long-acting morpholine acetal human NK-1 receptor antagonist. 980

We have developed a non-peptide compound, HSP-117, antagonist of the tachykinin NK-1 receptor. Binding of 3H-substance P (SP) to the membranes of IM-9 cells was inhibited by the antagonists HSP-117 and CP-99,994, the inhibitory activity of HSP-117 being about 50-fold that of CP-99,994. The SP-induced firing responses of single neuron activity in slices of the nucleus tractus solitarius of ferrets were inhibited by 10 microM HSP-117. Intracerebroventricular injection of HSP-117 significantly inhibited retching and vomiting induced by copper sulphate and morphine and the inhibitory effect of HSP-117 on emesis was greater than that of CP-99,994. These results indicate that (1) HSP-117 is a potent anti-emetic agent, blocking NK-1 receptors in the nucleus tractus solitarius and (2) NK-1 receptors in the nucleus tractus solitarius play an important role in emesis induced by broad-spectrum emetic stimuli.
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PMID:Anti-emetic effects of a novel NK-1 receptor antagonist HSP-117 in ferrets. 1021 84

Nausea and vomiting (emesis) occur under a variety of conditions in response to activation of one or more emetic triggers. The act of vomiting is coordinated by neuronal circuitry located in the brain stem between the obex and the retrofacial nucleus, including the region extending from the nucleus of the solitary tract through the lateral tegmental field of the reticular formation to the ventrolateral medulla. The area postrema, medullary midline, and certain higher brain centers are also important for vomiting. The sensation of nausea is thought to involve the cerebral cortex. The most effective near-term treatment for combating nausea and vomiting associated with cyclic vomiting syndrome may come from experimental drugs (NK-1 receptor antagonists, 5-HT1A receptor agonists) or P6 acustimulation, which have been shown to combat nausea and vomiting in response to a broad spectrum of emetic challenges and thus presumably act on central emetic mechanisms.
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PMID:Central mechanisms of vomiting. 1049 38

The gut smooth muscle in the intact conscious state exhibits three distinct types of contractions: rhythmic phasic contractions, tone, and ultrapropulsive contractions. The motility functions of these contractions differ markedly. The phasic contractions mix and propel the ingested food in an orderly fashion so that the nutrients can be absorbed. The ultrapropulsive contractions are of two types, giant migrating contractions (GMCs) and retrograde giant contractions (RGCs). GMCs produce mass movements in the caudal direction and RGCs in the oral direction. GMCs are associated with the symptoms of diarrhea, abdominal cramping, tenesmus, and urgency of defecation. The RGCs regurgitate the contents of the upper small intestine into the stomach in preparation of their expulsion by the somatomotor response. Tachykinins and their receptors are strategically located on the enteric neurons and smooth muscle cells to regulate the above contractions. Recent findings show that NK-1 receptors located on colonic circular smooth muscle cells may mediate colonic GMCs, whereas NK-3 receptors located on presynaptic neurons may mediate the small intestinal GMCs. The molecular and cellular mechanisms of stimulation of RGCs are not known. NK-1 receptor antagonists have shown potential therapeutic effects on vomiting induced by a variety of stimuli in experimental animals.
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PMID:Tachykinins and in vivo gut motility. 1049 50

Substance P (SP) is a member of the tachykinin family of bioactive peptides and has highest affinity for the NK-1 receptor. We have developed the non-peptide compound HSP-117 as a selective antagonist of the NK-1 receptor. Binding of 3H-SP to the membranes of IM-9 cells was inhibited by the antagonists HSP-117 and CP-99,994, the inhibitory activity of HSP-117 being 50-fold that of CP-99,994. The SP-induced firing responses of single neuron activity in slices of the nucleus tractus solitarius of ferrets were inhibited by 10 microM HSP-117. Intracerebroventricular injection of HSP-117 significantly inhibited retching and vomiting induced by copper sulphate and morphine and the inhibitory effect of HSP-117 on emesis was greater than that of CP-99,994. Moreover, emesis induced by copper sulphate and morphine were inhibited by the microinjection of HSP-117 and CP-99,994 into the area postrema and by lesion of the area postrema. These results indicate that HSP-117 is a potent anti-emetic agent, blocking NK-1 receptors in the area postrema and that NK-1 receptors in the area postrema play an important role in emesis induced by broad-spectrum emetic stimuli.
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PMID:[The role of tachykinin NK-1 receptors in emetic action in the area postrema of ferrets]. 1062 82

The regioselective dibenzylphosphorylation of 2 followed by catalytic reduction in the presence of N-methyl-D-glucamine afforded 2-(S)-(1-(R)-(3, 5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(5-(2- phosphoryl-3-oxo-4H,-1,2,4-triazolo)methylmorpholine, bis(N-methyl-D-glucamine) salt, 11. Incubation of 11 in rat, dog, and human plasma and in human hepatic subcellular fractions in vitro indicated that conversion to 2 would be expected to occur in vivo most readily in humans during hepatic circulation. Conversion of 11 to 2 occurred rapidly in vivo in the rat and dog with the levels of 11 being undetectable within 5 min after 1 and 8 mg/kg doses iv in the rat and within 15 min after 0.5, 2, and 32 mg/kg doses iv in the dog. Compound 11 has a 10-fold lower affinity for the human NK-1 receptor as compared to 2, but it is functionally equivalent to 2 in preclinical models of NK-1-mediated inflammation in the guinea pig and cisplatin-induced emesis in the ferret, indicating that 11 acts as a prodrug of 2. Based in part on these data, 11 was identified as a novel, water-soluble prodrug of the clinical candidate 2 suitable for intravenous administration in humans.
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PMID:Phosphorylated morpholine acetal human neurokinin-1 receptor antagonists as water-soluble prodrugs. 1073 56

The role of tachykinin NK-1 receptors in the area postrema (AP) in emesis was examined in ferrets. Strong c-fos-like immunoreactivity was observed in the AP and nucleus tractus solitalius (NTS) in cisplatin (10 mg/kg, i.p.)-treated animals, but not in control animals. The number of the central emetogen morphine-induced vomits and retches was remarkably reduced (95%) and that of the peripheral emetogen copper sulphate-induced vomits was significantly (54%) reduced by AP lesion. Pretreatment with the tachykinin NK-1 receptor antagonists HSP-117 (1.0 microg) and CP-99,994 (7.5 microg) into the AP decreased the numbers of vomits and retches induced by morphine and copper sulphate. These results suggest that NK-1 receptors in the AP are involved in the mechanism of emesis induced by morphine and copper sulphate.
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PMID:The role of tachykinin NK-1 receptors in the area postrema of ferrets in emesis. 1082 52

Emesis is one of the most unpleasant and debilitating side effects of anticancer chemotherapy. In acute emesis (vomiting occurring 0-24 hours after chemotherapy administration), the 5-HT3 receptor antagonists and corticosteroids are highly effective, with few significant side effects, and can safely be combined. Delayed emesis (vomiting occurring >24 hours after chemotherapy administration), however, is both not well understood and less well controlled. Studies have yielded conflicting results concerning the use of 5-HT3 receptor antagonists alone in delayed emesis. The data of NK-1 receptor antagonists in the control of acute emesis, although promising, need confirmation in a properly designed study.
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PMID:A new class of antiemetics: the NK-1 receptor antagonists. 1088 11

This article provides a brief overview of the history of substance P from its discovery in the 1930s to the present day. The development of substance P receptor agonists and antagonists, and more recently the employment of transgenic mice, provide a framework to explore the functional role of substance P. Chronic inflammation and pain are associated with a number of diseases, and it has been proposed that substance P, released from primary afferent nerve endings play a role in these conditions. Recent developments with substance P antagonists have demonstrated the importance of substance P in several models of disease that span from asthma to chronic bronchitis; from cystitis, inflammatory bowel disease to migraine; emesis, depression, pain and seizures. Advancements in the knowledge of the role of substance P, its agonists and antagonists could provide clinical solutions for a variety of chronic inflammatory conditions.
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PMID:Substance p. 1137 38

The pharmacokinetics, metabolism, and brain penetration of the neurokinin 1 (NK1) receptor antagonist (substance P receptor antagonist), aprepitant (MK-0869), were examined in ferrets. This species exhibits human-type NK1receptor pharmacology and is of proven value in the identification of clinically useful drugs for the treatment of chemotherapy-induced nausea and vomiting in humans. After a single p.o. dose of aprepitant at 1 or 2 mg/kg, plasma levels of the compound were between approximately 200 and 270 ng/ml, 24 h after dosing. In the brain cortex, concentrations of aprepitant reached between approximately 80 and 150 ng/g of tissue 24 h after dosing. The predominant radioactive component present in the plasma and the brain of ferrets at 24 or 48 h after a single oral dose of [14C]aprepitant at 3 mg/kg was the parent compound itself. The slow plasma clearance of aprepitant ( approximately 1.5 ml/min/kg) and its abundance in ferret brain were in accord with its efficacy in blocking the retching and vomiting at 24 and 48 h postdose when ferrets were challenged with the emetic anticancer drug, cisplatin. When aprepitant and some of its metabolites were assessed for their in vitro binding affinity to the human NK1receptor, aprepitant demonstrated the highest affinity. Collectively, these data suggested that aprepitant, rather than its metabolites, was responsible, primarily, for the antiemetic activity of this compound in the male ferret.
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PMID:Brain penetration of aprepitant, a substance P receptor antagonist, in ferrets. 1275 13


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