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Kevin Dinnell - One of the best experts on this subject based on the ideXlab platform.

W. Rycroft - One of the best experts on this subject based on the ideXlab platform.

  • 4 4 disubstituted cyclohexylamine NK1 Receptor Antagonists ii
    Bioorganic & Medicinal Chemistry Letters, 2002
    Co-Authors: Jason Matthew Elliott, Kevin Dinnell, Marc M. Kurtz, Gregory John Hollingworth, Gary G Chicchi, Laura Catherine Cooper, W. Rycroft, Jose L Castro, Mark P Ridgill, Duncan Shaw
    Abstract:

    A series of novel 4,4-disubstituted cyclohexylamines as NK(1) Receptor Antagonists is described: modifications to the amine moiety retain NK(1) Receptor binding affinity whilst disrupting I(Kr) affinity.

  • 2 aryl indole NK1 Receptor Antagonists optimisation of the 2 aryl ring and the indole nitrogen substituent
    Bioorganic & Medicinal Chemistry Letters, 2001
    Co-Authors: Kevin Dinnell, Kwei-lan Tsao, Marc M. Kurtz, Gregory John Hollingworth, Gary G Chicchi, Jason Matthew Elliott, W. Rycroft, Mark P Ridgill, Madhumeeta J Dhar, Angela Williams
    Abstract:

    Novel 2-aryl indole hNK1 Receptor ligands were prepared utilising palladium cross-coupling chemistry of a late intermediate as a key step. Compounds with high hNK1 Receptor binding affinity and good brain penetration (e.g., 9d) were synthesised.

  • in vitro and in vivo predictors of the anti emetic activity of tachykinin NK1 Receptor Antagonists
    European Journal of Pharmacology, 1997
    Co-Authors: Nadia M. J. Rupniak, David F Tattersall, Angela R Williams, Emma J Carlson, Jeffrey J Hale, W. Rycroft, Sander G Mills, Margaret A Cascieri, S Sadowski, Malcolm Maccoss
    Abstract:

    The ability of tachykinin NK1 Receptor Antagonists to inhibit GR73632 (d-Ala-[l-Pro9,Me-Leu8]substance P-(7–11))-induced foot tapping in gerbils was employed as an indirect measure of brain penetration and this was compared with their ability to prevent acute emesis induced by cisplatin in ferrets. (±)-GR203040 ((2S,3S and 2R,3R)-2-methoxy-5-tetrazol-1-yl-benzyl-(2-phenyl-piperidin-3-yl)-amine), CP-99,994 ((2S,3S)-cis-3-(2-methoxybenzylamino)-2-phenyl piperidine) dihydrochloride), and L-742,694 (2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-4-(5-(3-oxo-1,2,4-triazolo)methylmorpholine) potently inhibited GR73632-induced foot tapping (ID50≤0.85 mg/kg), and acute retching induced by cisplatin (ID50≤0.18 mg/kg). RPR100893 ((3aS,4S,7aS)-7,7-diphenyl-4-(2-methoxyphenyl)-2-[(S)-2-(2-methoxyphenyl)proprionyl] perhydroisoindol-4-ol) was not a potent antagonist of retching (ID50 4.1 mg/kg) or foot tapping (ID50>10 mg/kg). High doses (3–10 mg/kg) of CGP49823 ((2R,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-[(4-quinolinyl)methyl]-4-piperineamine) dihydrochloride), FK888 (N2-[(4R)-4-hydroxy-1-(1-methyl-1H-indol-3-yl)carbonyl-l-propyl]-N-methyl-N-phenylmethyl-l-3-(2-naphthyl)-alaninamide), and LY303870 ((R)-1-[N-(2-methoxybenzyl)acetylamino]-3-(1H-indol-3-yl)-2-[N-(2-(4-(piperidinyl)piperidin-1-yl)acetyl)amino]propane) were required to inhibit foot tapping; these agents were not anti-emetic in this dose range. SR140333 ((S)-1-{2-[3-(3,4-dichlorphenyl)-1 (3-isopropoxyphenylacetyl)piperidin-3-yl] ethyl}-4-phenyl-1 azaniabicyclo [2.2.2]octane; 3–10 mg/kg) failed to inhibit foot tapping or emesis. Affinities for the human and ferret tachykinin NK1 Receptor were highly correlated (r=0.93, P=0.0008). Inhibition of foot tapping in gerbils, but not NK1 Receptor binding affinity, predicted anti-emetic activity in ferrets (r=0.75, P<0.01). These findings confirm that the anti-emetic activity of tachykinin NK1 Receptor Antagonists is dependent on brain penetration.

  • in vitro and in vivo predictors of the anti emetic activity of tachykinin NK1 Receptor Antagonists
    European Journal of Pharmacology, 1997
    Co-Authors: Nadia M. J. Rupniak, David F Tattersall, Emma J Carlson, Jeffrey J Hale, W. Rycroft, Margaret A Cascieri, S Sadowski, Angela Williams, E Ber, Sander G Mills
    Abstract:

    The ability of tachykinin NK1 Receptor Antagonists to inhibit GR73632 (D-Ala-[L-Pro9,Me-Leu8]substance P-(7-11))-induced foot tapping in gerbils was employed as an indirect measure of brain penetration and this was compared with their ability to prevent acute emesis induced by cisplatin in ferrets. (+)-GR203040 ((2S,3S and 2R,3R)-2-methoxy-5-tetrazol-1-yl-benzyl-(2-phenyl-piperidin- 3-yl)-amine), CP-99,994 ((2S,3S)-cis-3-(2-methoxybenzylamino)-2-phenyl piperidine) dihydrochloride), and L-742,694 (2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-4-(5-(3-oxo-1,2, 4-triazolo)methylmorpholine) potently inhibited GR73632-induced foot tapping (ID50 10 mg/kg). High doses (3-10 mg/kg) of CGP49823 ((2R,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-[(4-quinolinyl)methyl] -4-piperineamine) dihydrochloride), FK888 (N2-[(4R)-4-hydroxy-1-(1-methyl-1H-indol-3-yl)carbonyl-L-propyl]-N-methy l-N-phenylmethyl-L-3-(2-naphthyl)-alaninamide), and LY303870 ((R)-1-[N-(2-methoxybenzyl)acetylamino]-3-(1H-indol-3-yl)-2-[N-(2-(4-(pi peridinyl)piperidin-1-yl)acetyl)amino]propane) were required to inhibit foot tapping; these agents were not anti-emetic in this dose range. SR140333 ((S)-1-[2-[3-(3,4-dichlorphenyl)-1 (3-isopropoxyphenylacetyl)piperidin-3-yl] ethyl]-4-phenyl-1 azaniabicyclo [2.2.2]octane; 3-10 mg/kg) failed to inhibit foot tapping or emesis. Affinities for the human and ferret tachykinin NK1 Receptor were highly correlated (r = 0.93, P = 0.0008). Inhibition of foot tapping in gerbils, but not NK1 Receptor binding affinity, predicted anti-emetic activity in ferrets (r = 0.75, P < 0.01). These findings confirm that the anti-emetic activity of tachykinin NK1 Receptor Antagonists is dependent on brain penetration.

  • tachykinin NK1 Receptor Antagonists act centrally to inhibit emesis induced by the chemotherapeutic agent cisplatin in ferrets
    Neuropharmacology, 1996
    Co-Authors: F D Tattersall, W. Rycroft, Barbara Francis, David Pearce, Kevin John Merchant, Angus Murray Macleod, T Ladduwahetty, Linda Elizabeth Keown, Christopher John Swain, R Baker
    Abstract:

    These studies have compared the pharmacological profile of two non-peptide human type neurokinin1 (hNK1) Receptor selective Antagonists, L-741,671 and a quaternised compound L-743,310. In radioligand binding studies L-741,671 and L-743,310 had high affinity for ferret and cloned hNK1 Receptors [Ki (nM) ferret 0.7 and 0.1; human 0.03 and 0.06, respectively] but low affinity for rodent NK1 Receptors [Ki (nM) 64 and 17, respectively] suggesting that ferret Receptors have hNK1-like binding pharmacology. Studies in vivo showed that L-741,671 and L-743,310 had equivalent functional activity in the periphery (ID50s of 1.6 and 2 micrograms/kg i.v., respectively) as measured by inhibition of plasma protein extravasation evoked in the oesophagus of guinea pigs by resiniferatoxin (7 nmol/kg i.v.). Using an in situ brain perfusion technique in anaesthetised rats, L-741,671 was shown to be much more brain penetrant than the quaternary compound L-743,310 which had an entry rate similar to the poorly brain penetrant plasma marker inulin. These compounds thus provided an opportunity to compare the anti-emetic effects of equi-active hNK1 Receptor Antagonists with and without brain penetration to central NK1 Receptor sites. When tested against cisplatin-induced emesis in ferrets, L-741,671 (0.3, 1 and 3 mg/kg i.v.) produced marked dose-dependent inhibition of retching and vomiting but L-743,310 was inactive at 3 and 10 micrograms/kg i.v. In contrast, direct central injection of L-741,671 and L-743,310 (30 micrograms) into the vicinity of the nucleus tractus solitarius or L-743,310 (200 micrograms) intracisternally was shown to inhibit retching and vomiting induced by i.v. cisplatin. L-741,671 and L-743,310 had equivalent functional activity, at the same dose, against cisplatin-induced emesis when injected centrally. These observations indicated that had L-743,310 penetrated into the brain after systemic administration it would have been active in the cisplatin-induced emesis assay and so show that brain penetration is essential for the anti-emetic action of systemically administered NK1 Receptor Antagonists.

Marc M. Kurtz - One of the best experts on this subject based on the ideXlab platform.

Gary G Chicchi - One of the best experts on this subject based on the ideXlab platform.

John A. Rudd - One of the best experts on this subject based on the ideXlab platform.

  • the differential antiemetic properties of glp 1 Receptor antagonist exendin 9 39 in suncus murinus house musk shrew
    Neuropharmacology, 2014
    Co-Authors: Sze Wa Chan, Zengbing Lu, Chi Kong Yeung, John A. Rudd
    Abstract:

    Abstract 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), 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.

  • the role of tachykinins and the tachykinin NK1 Receptor in nausea and emesis
    Handbook of experimental pharmacology, 2004
    Co-Authors: Paul L R Andrews, John A. Rudd
    Abstract:

    Nausea and vomiting are both components of the body’s defensive system to protect against the effects of accidentally ingested toxins. Whilst these responses have survival value in the wild, they can also be induced by diseases and disease treatments with one of the most unpleasant examples being the treatment of cancer using cytotoxic drugs and radiation. Understanding the mechanisms by which this occurs has been a major impetus to the identification of novel anti-emetic agents. The recent licensing of an NK1 Receptor antagonist for the treatment of chemotherapy-induced emesis provides the first example of a drug acting to block the effects of substance P. Whilst the blockade of emesis by selective NK1 Receptor Antagonists provides the most powerful evidence implicating substance P in emesis there is a considerable body of supporting evidence including: presence of substance P (usually by immunohistochemistry) in relevant sites (e.g. vagal afferents, nucleus tractus solitarius, gastrointestinal mucosa); presence of NK1, Receptors in relevant sites (e.g. nucleus tractus solitarius); induction of emesis by administration of NK1 Receptor agonists. Pre-clinical studies in a variety of species revealed the broad-spectrum anti-emetic effects of NK1 Receptor Antagonists against stimuli including the anti-cancer agent cisplatin (acute and delayed phases), radiation, opioids, copper sulphate, apomorphine, motion and electrical stimulation of abdominal vagal afferents. Species differences in response to NK1 Receptor Antagonists and species-specific iso-forms of the Receptor are discussed and the potential implications for transfer of data from these animal models to humans reviewed. The spectrum of antiemetic effects against stimuli acting via both peripheral and centrally acting emetic stimuli, a requirement for brain penetration and blockade of emesis by microinjection of Antagonists into the brain stem all support a central site of action with the nucleus tractus solitarius and the vicinity of the Botzinger complex being the favoured locations although definitive studies are awaited. Evidence for a contribution from a peripheral site in the delayed phase of cytotoxic druginduced emesis is reviewed. The unique pre-clinical profile and especially the observation that NK1, Receptor Antagonists could block both the acute and delayed phase of cisplatin-induced emesis prompted clinical trials of a number of agents [CJ11974 (ezlopitant), GR205171 (vofopitant), MK869/L754030 (aprepi-tant)] in patients undergoing chemotherapy. These studies and others in motion and post-operative nausea and vomiting are reviewed in detail. In general the trials in chemotherapy show NK1 Receptor Antagonists have demonstrable efficacy against acute (first 24 h after therapy) emesis when given alone and enhance the efficacy of 5-hydroxytryptamine3 Receptor Antagonists and dexamethasone when given in combination. Of particular clinical significance is the efficacy of NK1 Receptor Antagonists given in combination with dexamethasone to reduce emesis in the delayed phase (days 2–5) as this phase of emesis is poorly con trolled using current treatments. Efficacy against nausea has been reported but to date the effects appear less clear than against emesis and further studies are required. The availability of NK1 Receptor Antagonists in the clinic will provide a useful tool to further investigate the involvement of NK1 Receptors in emesis and to explore the roles of central and peripheral substance P in health and disease.

  • inhibition of emesis by tachykinin NK1 Receptor Antagonists in suncus murinus house musk shrew
    European Journal of Pharmacology, 1999
    Co-Authors: John A. Rudd, Man P Ngan
    Abstract:

    Abstract The anti-emetic potential of CP-122,721 ((+)-2S,3S)-3-(2-methoxy-5-trifluoromethoxybenzyl)amino-2-phenylpiperidine), CP-99,994 ((+)-(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine), CP-100,263 ((−)-(2R,3R)-3-(2-methoxybenzylamino)-2-phenylpiperidine), RP 67580 ((3R, 7aR)-7, 7-diphenyl-2-[1-imino-2-(2-methoxyphenyl)ethyl] po-hydroisoindol-4-one), FK 888 (N2-[(4R)-4-hydroxy-1-(1-methyl-1H-indole-3-yl)carbonyl- l -propyl]-N-methyl-N-phenylmethyl-l-3-(2-naphthyl)-alaninamide) and GR 82334 ([ d -Pro9{spiro-g-lactam}Leu10]-physalaemin-(1–11)) was investigated to inhibit nicotine (5 mg/kg, s.c.)-, copper sulphate pentahydrate (120 mg/kg, intragastric)- and motion (4 cm horizontal displacement at 1 Hz for 5 min)-induced emesis in Suncus murinus. A 30 min intraperitoneal pre-treatment with CP-122,721, CP-99,994, RP 67580 and FK 888 significantly (P

  • inhibition of emesis by tachykinin NK1 Receptor Antagonists in suncus murinus house musk shrew
    European Journal of Pharmacology, 1999
    Co-Authors: John A. Rudd, Man P Ngan, Man K Wai
    Abstract:

    The anti-emetic potential of CP-122,721 ((+)-2S,3S)-3-(2-methoxy-5-trifluoromethoxybenzyl)amino-2-phenylpiperidine), CP-99,994 ((+)-(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine), CP-100,263 ((−)-(2R,3R)-3-(2-methoxybenzylamino)-2-phenylpiperidine), RP 67580 ((3R, 7aR)-7, 7-diphenyl-2-[1-imino-2-(2-methoxyphenyl)ethyl] po-hydroisoindol-4-one), FK 888 (N2-[(4R)-4-hydroxy-1-(1-methyl-1H-indole-3-yl)carbonyl-l-propyl]-N-methyl-N-phenylmethyl-l-3-(2-naphthyl)-alaninamide) and GR 82334 ([d-Pro9{spiro-g-lactam}Leu10]-physalaemin-(1–11)) was investigated to inhibit nicotine (5 mg/kg, s.c.)-, copper sulphate pentahydrate (120 mg/kg, intragastric)- and motion (4 cm horizontal displacement at 1 Hz for 5 min)-induced emesis in Suncus murinus. A 30 min intraperitoneal pre-treatment with CP-122,721, CP-99,994, RP 67580 and FK 888 significantly (P<0.05) antagonized nicotine-induced emesis with ID50 values of 2.1, 2.3, 13.5 and 19.2 mg/kg, respectively CP-100,263, the less active enantiomer of CP-99,994, was inactive at doses up to 10 mg/kg. Infusion of GR 82334, CP-122,721, CP-99,994 and FK 888 into the dorsal vagal complex of the hindbrain also antagonized nicotine-induced emesis yielding ID50 values of 1.1, 3.0, 3.3 and 58.0 μg/dorsal vagal complex, respectively RP 67580 and CP-100,263 were inactive. RP 67580 and FK 888 failed to antagonize copper sulphate-induced emesis but CP-122,721 and CP-99,994 were active yielding ID50 values of 2.2 and 3.0 mg/kg, i.p., respectively. CP-99,994 also completely prevented motion-induced emesis at 10 mg/kg, i.p. (P<0.05) and RP 67580 produced a significant reduction of motion-induced emesis at 10 mg/kg, i.p. (P<0.05). These studies provide evidence of a central site of action of tachykinin NK1 Receptor Antagonists to inhibit nicotine-induced emesis in S. murinus and confirm the broad profile of inhibitory action. The rank order of potency of the Antagonists following the intra-dorsal vagal complex administration suggests that the S. murinus tachykinin NK1 Receptor has a unique pharmacological profile.