Anti-emetic profile of a non-peptide neurokinin NK1 receptor antagonist, CP-99,994, in ferrets

doi:10.1016/0014-2999(93)90673-6

European Journal of Pharmacology

Volume 249, Issues 1–2, 2 November 1993, Pages R3-R4

https://doi.org/10.1016/0014-2999(93)90673-6 Get rights and content

Abstract

In the ferret, 5-HT₃ receptor antagonists are effective in controlling emesis produced by cytotoxic agents or radiation. To investigate the possibility that substance P has a role, as well as 5-HT, in the emetic reflex pathway, we have examined the anti-emetic effects of a NK₁ receptor antagonist (racemic CP-99,994) in the ferret. Racemic CP-99,994 was effective against a range of emetogens, comprising cytotoxic drugs, radiation, morphine, ipecacuanha and copper sulphate.

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Selectivity of 5-HT₃ receptor antagonists and anti-emetic mechanisms of action
Anti-Cancer Drugs
(1992)

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SP induces vomiting by binding to NK-1 receptors, which are expressed in the abdominal vagus, the NTS and the AP [16]. Further evidence of the role of SP in vomiting was provided by investigating the antiemetic effect of SP antagonists (SPAs) in animal models [17–20]. Of note, only SPAs that could penetrate into the brain were effective [21].
Substance P (SP) is involved in the development of postoperative nausea and vomiting (PONV). It is hydrolyzed by angiotensin-converting enzyme (ACE). Centrally acting ACE inhibitors (CACE-Is) are widely used in the perioperative period. The current evidence showed CACE-Is could upregulate SP level in the central nervous system which may contribute to the occurrence of PONV in 0–72 h. Here, we present our hypothesis that the use of CACE-Is in the perioperative period may increase patients’ risk for both early (0–24 h) and late (24–72 h) PONV. The identification of this new risk factor may improve patients’ risk assessment and thus lead to better prophylaxis strategies for PONV that are base on risk stratification.
The differential antiemetic properties of GLP-1 receptor antagonist, exendin (9-39) in Suncus murinus (house musk shrew)
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It also antagonises lithium chloride-induced conditioned gaping (a putative model of nausea) in rats when combined with a subthreshold dose of cannabidiolic acid (Rock and Parker, 2013). Tachykinin NK1 receptor antagonists have broad spectrum anti-emetic activity against various emetic stimuli including cisplatin, radiation, copper sulphate, ipecacuanha, morphine (Bountra et al., 1993; Gardner et al., 1995, 1996), apomorphine (Watson et al., 1995), loperamide (Watson et al., 1995), and motion (Lucot et al., 1997). Previous studies in our laboratories have shown that subcutaneous administration of CP-99,994 significantly reduced emesis induced by cisplatin and nicotine (Lau et al., 2005; Rudd et al., 1999b).
The use of glucagon-like peptide-1 (7–36) amide (GLP-1) receptor agonists for the treatment of type 2 diabetes mellitus is commonly associated with nausea and vomiting. Previous studies using Suncus murinus revealed that the GLP-1 receptor agonist, exendin-4, induces emesis via the brainstem and/or hypothalamus. The present study investigated the mechanism of exendin-4-induced emesis in more detail. Ondansetron (1 mg/kg, s.c.) and CP-99,994 (10 mg/kg, s.c) failed to reduce emesis induced by exendin-4 (3 nmol, i.c.v.), suggesting that 5-HT₃ and NK₁ receptors are not involved in the mechanism. In other studies, the GLP-1 receptor antagonist, exendin (9–39), antagonised emesis and c-Fos expression in the brainstem and the paraventricular hypothalamus induced by the chemotherapeutic drug cisplatin (30 mg/kg, i.p.; p < 0.05), but not the emesis induced by nicotine (5 mg/kg, s.c.; p > 0.05), or copper sulphate pentahydrate (120 mg/kg, p.o.; p > 0.05). GLP-1 receptors may therefore represent a potential target for drugs to prevent chemotherapy-induced emesis in situations where 5-HT₃ and NK₁ receptor antagonists fail.
Molecular mechanisms of 5-HT<inf>3</inf> and NK<inf>1</inf> receptor antagonists in prevention of emesis
2014, European Journal of Pharmacology
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NK1 receptor antagonists were shown to be effective against emesis induced by a variety of emetogens, including cisplatin in animal models of emesis. The results paved the way for NK1 receptor antagonists to be recognized as new therapeutic agents for the treatment of CINV in cancer patients (Bountra et al., 1993). The first NK1 receptor antagonists were developed in the 1980s; they were peptides (Engberg et al., 1981) or peptidomimetics (Quartara and Maggi, 1997a) based on SP.
Nausea and vomiting are major side effects of chemotherapy and one key reason for non-compliance with cancer treatment. The introduction of 5-HT₃ receptor antagonists in the 1990s was a major advance in the prevention of acute emesis, and highlighted the critical role of serotonin in the emetic response. The next major advance in the treatment of chemotherapy induced nausea and vomiting (CINV) occurred in 2003 with the introduction of aprepitant, a tachykinin 1 (NK₁) receptor antagonist. Aprepitant not only reduced acute emesis but also helped in the reduction of delayed emesis. Also in 2003, palonosetron, a second generation 5-HT₃ receptor antagonist became available. Unlike the first generation 5-HT₃ receptor antagonists, palonosetron demonstrated efficacy in preventing both acute and delayed emesis. This review focuses on the mechanism of action of 5-HT₃ and NK₁ receptor antagonists in acute and delayed CINV prevention. We discuss first, the medicinal chemistry that led to the discovery of these antagonists to underline their common structural features. Second, we discuss their performance in the clinic and what it tells us about the emetic response. Finally, we present recent mechanistic studies that help provide a rationale for efficacy differences between palonosetron and other 5-HT₃ receptor antagonists in the clinic. In vitro and in vivo experiments have shown that palonosetron can inhibit substance P-mediated responses, presumably through its unique interactions with the 5-HT₃ receptor. The crossroads of acute and delayed emesis seem to include interactions among the 5-HT₃ and NK₁ receptor signaling pathways and inhibitions of these interactions could lead to improved treatment of CINV.
Broad-spectrum antiemetic potential of the L-type calcium channel antagonist nifedipine and evidence for its additive antiemetic interaction with the 5-HT<inf>3</inf> receptor antagonist palonosetron in the least shrew (Cryptotis parva)
2014, European Journal of Pharmacology
Citation Excerpt :
More recent research effort in antiemetic drug development has focused on producing receptor-selective antagonists that could have broad-spectrum antiemetic potential with fewer side-effects. In fact the development of NK1 receptor antagonists in the early 1990s introduced the notion of a universal antiemetic in the realm of frequently used emesis models such as the ferret (Bountra et al., 1993). However, such observed broad-spectrum antiemetic efficacy of selective NK1 receptor antagonists in larger species unfortunately failed to fully translate either in the clinic for patients, or in the laboratory for the smaller species, the least shrew.
Cisplatin-like chemotherapeutics cause vomiting via release of multiple neurotransmitters (dopamine, serotonin (5-HT), or substance P (SP)) from the gastrointestinal enterochromaffin cells and/or the brainstem via a calcium dependent process. Diverse channels in the plasma membrane allow extracellular Ca²⁺ entry into cells for the transmitter release process. Agonists of 5-HT₃ receptors increase calcium influx through both 5-HT₃ receptors and L-type Ca²⁺ channels. We envisaged that L-type calcium agonists such as FPL 64176 should cause vomiting and corresponding antagonists such as nifedipine would behave as broad-spectrum antiemetics. Administration of FPL 64176 did cause vomiting in the least shrew in a dose-dependent fashion. Nifedipine and the 5-HT₃ receptor antagonist palonosetron, potently suppressed FPL 64176-induced vomiting, while a combination of ineffective doses of these antagonists was more efficacious. Subsequently, we investigated the broad-spectrum antiemetic potential of nifedipine against diverse emetogens including agonists of serotonergic 5-HT₃- (e.g. 5-HT or 2-Me-5-HT), SP tachykinin NK₁- (GR73632), dopamine D₂- (apomorphine or quinpirole), and cholinergic M₁- (McN-A-343) receptors, as well as the non-specific emetogen, cisplatin. Nifedipine by itself suppressed vomiting in a potent and dose-dependent manner caused by the above emetogens except cisplatin. Moreover, low doses of nifedipine potentiated the antiemetic efficacy of non-effective or semi-effective doses of palonosetron against vomiting caused by either 2-Me-5-HT or cisplatin. Thus, our findings demonstrate that activation of L-type calcium channels causes vomiting, whereas blockade of these ion channels by nifedipine-like antagonists not only provides broad-spectrum antiemetic activity but can also potentiate the antiemetic efficacy of well-established antiemetics such as palonosetron. L-type calcium channel antagonists should also provide antiemetic activity against drug-induced vomiting as well as other emetogens including bacterial and viral proteins.
Rolapitant (SCH 619734): A potent, selective and orally active neurokinin NK1 receptor antagonist with centrally-mediated antiemetic effects in ferrets
2012, Pharmacology Biochemistry and Behavior
Citation Excerpt :
Neurokinin NK1 receptors have been shown to play a role in a variety of behavioral responses in both animals and humans which has lead to the development of selective antagonists for this receptor (for review see Duffy, 2004). Principal among the properties of NK1 antagonists is their inhibitory effects against emesis induced by a variety of emetogenic stimuli (Bountra et al., 1993; Tattersall et al., 1993) resulting in the NK1 antagonist aprepitant (Emend®) being approved and marketed for the treatment of chemotherapy-induced nausea and vomiting (CINV) and post-operative nausea and vomiting (PONV) (Diemunsch et al., 2009; Rupniak and Kramer, 1999; Diemunsch and Grelot, 2000). A variety of NK1 antagonists have been consistently shown to demonstrate a robust, dose-related, anti-emetic profile across a diverse range of animal models (Watson et al., 1995; Rudd et al., 1996, 1999; Tattersall et al., 1994, 1996; Gardner et al., 1995, 1996; Singh et al., 1997).
NK1 receptor antagonists have been shown to have a variety of physiological and potential therapeutic effects in animal models and in humans. The present studies demonstrate that Rolapitant (SCH 619734, (5S)-8(S)-[[1(R)-[3,5 bis(trifluoromethyl)phenyl]ethoxy]methyl]-8-phenyl-1,7-diazaspiro[4,5]decan-2-one) is a selective, bioavailable, CNS penetrant neurokinin NK1 receptor antagonist that shows behavioral effects in animals models of emesis. In vitro studies indicate that rolapitant has a high affinity for the human NK1 receptor of 0.66 nM and high selectivity over the human NK2 and NK3 subtypes of > 1000-fold, as well as preferential affinity for human, guinea pig, gerbil and monkey NK1 receptors over rat, mouse and rabbit. Rolapitant is a functionally competitive antagonist, as measured by calcium efflux, with a calculated Kb of 0.17 nM. Rolapitant reversed NK1 agonist-induced foot tapping in gerbils following both intravenous and oral administration up to 24 hours at a minimal effective dose (MED) of 0.1 mg/kg. Rolapitant was active at 0.1 and 1 mg/kg in both acute and delayed emesis models in ferrets, respectively, consistent with clinical data for other NK1 antagonists. Clinical efficacy of anti-emetics is highly correlated with efficacy in the ferret emesis model, suggesting rolapitant is a viable clinical candidate for this indication.

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Rapid communicationAnti-emetic profile of a non-peptide neurokinin NK1 receptor antagonist, CP-99,994, in ferrets

Abstract

Regul. Pept. Suppl.

Selectivity of 5-HT3 receptor antagonists and anti-emetic mechanisms of action

Anti-Cancer Drugs

Rapid communication
Anti-emetic profile of a non-peptide neurokinin NK₁ receptor antagonist, CP-99,994, in ferrets

Selectivity of 5-HT₃ receptor antagonists and anti-emetic mechanisms of action