benzofurans and Vomiting

Serotonin receptor (5-HT3) antagonists provide effective antiemetic therapy in cancer patients receiving emetogenic chemotherapy, such as cisplatin. Animal studies have shown that 5-HT3 receptor antagonists also have antiemetic activity in ipecac-induced emesis. The authors investigated the antiemetic activity of zatosetron maleate, a 5-HT3 receptor antagonist, on ipecac-induced emesis in dogs and healthy men. They also evaluated the effect of ipecac administration on serotonin release and metabolism by measuring urinary 5-hydroxyindoleacetic acid (5-HIAA) excretion in healthy men. In separate randomized, placebo-controlled trials, 20 dogs received zatosetron intravenously and eight healthy men received zatosetron (50 mg) orally, followed by ipecac syrup. In both trials, emetic response to ipecac was recorded, including the number and time of vomits and retches. Zatosetron treatment inhibited and delayed ipecac-induced emesis in both groups. In dogs, zatosetron inhibited ipecac-induced emesis in a dose-dependent manner with a 100-micrograms/kg dose producing complete inhibition. In men, zatosetron administration resulted in fewer emetic episodes after ipecac than had occurred with placebo administration (P = .03); vomiting was completely inhibited by zatosetron. In men, ipecac administration did not affect the urinary 5-HIAA/creatinine ratio (mg/g) or 5-HIAA excretion rate (microgram/hour). Our study demonstrates that zatosetron has similar efficacy on ipecac-induced emesis in healthy men, as has been shown previously with other 5-HT3 receptor antagonists in chemotherapy-induced emesis in cancer patients. We did not observe the increase of urinary 5-HIAA in our study with ipecac-induced emesis, however, as has been described previously in cisplatin-induced emesis.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Administration, Oral; Adult; Animals; Benzofurans; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Dogs; Female; Humans; Hydroxyindoleacetic Acid; Injections, Intravenous; Ipecac; Male; Middle Aged; Serotonin Antagonists; Vomiting

RG 12915 is a potent, selective 5-HT3 receptor antagonist with a biologic half-life of 11-20 hours. RG 12915 prevents cisplatin-induced emesis in ferrets at doses of 0.03 mg/kg. Animal toxicology studies permitted safe testing in humans at doses of up to 2.0 mg/kg. This dose-ranging trial of intravenous RG 12915 was performed to determine the optimal dosage and adverse effects and to observe for antiemetic effects in patients receiving anticancer chemotherapy.. Twenty-six patients receiving chemotherapy likely to cause vomiting received a single intravenous dose of RG 12915 at a rate of 3 ml/minute beginning 60 minutes before chemotherapy. Four dose levels were explored: 0.25, 0.50, 1.0, and 2.0 mg/kg.. No dose-limiting toxicities were observed. All adverse effects were mild and transient and included discomfort at the infusion site, hyperglycemia, headache, serum aspartate transaminase (AST) and alanine transaminase (ALT) elevations, and sedation. Antiemetic efficacy was seen in patients receiving cisplatin at doses of greater than or equal to 100 mg/m2.. RG 12915 can be administered safely at the dose levels explored. Single intravenous doses of RG 12915 prevented or lessened emesis caused by chemotherapy, including cisplatin given at doses of greater than or equal to 100 mg/m2. RG 12915 warrants further testing. Of the doses tested, the 2.0 mg/kg dose is the most appropriate for further exploration.

Topics: Adolescent; Adult; Antiemetics; Antineoplastic Agents; Benzofurans; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Cisplatin; Dose-Response Relationship, Drug; Female; Humans; Infusions, Intravenous; Male; Middle Aged; Nausea; Neoplasms; Serotonin Antagonists; Vomiting

Previously, we designed, synthesized, and evaluated a series of quinolone-benzofuran derivatives as multitargeted anti-Alzheimer's disease (anti-AD) compounds, and we discovered that WBQ5187 possesses superior anti-AD bioactivity. In this work, we investigated the pharmacokinetics of this new molecule, as well as its therapeutic efficacy in restoring cognition and neuropathology, in the APP/PS1 mouse model of AD. Pharmacokinetic analyses demonstrated that WBQ5187 possessed rational oral bioavailability, metabolic stability, and excellent blood-brain barrier (BBB) permeability. Pharmacodynamics studies indicated that a 12-week treatment with the lead compound at doses of 40 mg/kg or higher significantly enhanced the learning and memory performance of the APP/PS1 transgenic mice, and the effect was more potent than that of clioquinol (CQ). Furthermore, WBQ5187 notably reduced cerebral β-amyloid pathology, gliosis, and neuronal cell loss and increased the levels of cAMP in the hippocampus of these mice. The surrogate measures of emesis indicated that WBQ5187 had no effect at its cognitive effective doses. Overall, our results demonstrated that this compound markedly improves cognitive and spatial memory functions in AD mice and represents a promising pharmaceutical agent with potential for the treatment of AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Anesthetics, General; Animals; Benzofurans; Biological Availability; Blood-Brain Barrier; Brain Chemistry; Clioquinol; Cyclic AMP; Disease Models, Animal; Drug Evaluation, Preclinical; Gliosis; Hippocampus; Male; Maze Learning; Memory Disorders; Mice; Mice, Inbred C57BL; Mice, Transgenic; Nausea; Neuroprotective Agents; Phosphodiesterase 4 Inhibitors; Resorcinols; Second Messenger Systems; Vomiting

The effects of a novel tachykinin NK1-receptor antagonist HSP-117 [(2S,3S)-3-[(5-isopropyl-2,3-dihydrobenzofuran-7-yl)methyl]amino-2-phenylpiperidine dihydrochloride] on cisplatin-induced pica, i.e., the eating of nonnutritive substances such as kaolin were examined in rats. HSP-117 inhibited kaolin intake in a dose-dependent manner for 2 days. The 5-HT3-receptor antagonist ondansetron inhibited only on the first day, but not on the second day. These results indicate that the cisplatin-induced kaolin intake on the first day is related to both 5-HT3- and NK1 receptors, while only the NK1 receptor is involved on the second day. Thus, cisplatin-induced continuous pica in rats represents a useful model of not only acute but also delayed emesis.

Topics: Animals; Antineoplastic Agents; Benzofurans; Cisplatin; Humans; Neurokinin-1 Receptor Antagonists; Pica; Piperidines; Rats; Rats, Wistar; Vomiting

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.

Topics: Animals; Antiemetics; Antineoplastic Agents; Benzofurans; Chemoreceptor Cells; Cisplatin; Copper Sulfate; Drug Interactions; Ferrets; Fourth Ventricle; Male; Medulla Oblongata; Morphine; Narcotics; Neurokinin-1 Receptor Antagonists; Neurons; Piperidines; Proto-Oncogene Proteins c-fos; Radioligand Assay; Receptors, Neurokinin-1; Solitary Nucleus; Substance P; Tachykinins; Tritium; Vomiting

The synthesis and pharmacological profile of a novel series of 7-methoxybenzofuran-4-carboxamides is described. Some of these compounds were found to be potent inhibitors of phosphodiesterase type 4 (PDE4).

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Administration, Oral; Animals; Asthma; Benzamides; Benzofurans; Cyclic Nucleotide Phosphodiesterases, Type 4; Eosinophilia; Guinea Pigs; Inhibitory Concentration 50; Phosphodiesterase Inhibitors; Pyridines; Rolipram; Structure-Activity Relationship; Vomiting

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.

Topics: Animals; Antiemetics; Benzofurans; Copper Sulfate; Ferrets; Medulla Oblongata; Morphine; Piperidines; Receptors, Neurokinin-1; Solitary Nucleus; Stereoisomerism; Vomiting

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.

Topics: Animals; Antiemetics; Benzofurans; Brain Stem; Cerebral Ventricles; Copper Sulfate; Emetics; Ferrets; In Vitro Techniques; Injections, Intraventricular; Male; Membrane Potentials; Morphine; Neurokinin-1 Receptor Antagonists; Piperidines; Substance P; Vomiting

Recently discovered serotonin3 (5-HT3) receptor antagonists are potent antiemetics in cytotoxic drug-induced vomiting. The specific site where 5-HT3 receptor antagonists act to abolish emesis is controversial. The major objective of this study was to determine whether the antiemetic effect of 5-HT3 receptor antagonists is exerted in the brain areas that reside inside or outside of the blood-brain barrier. Tropisetron, zatosetron (LY277359 maleate) and its quaternary analog zatosetron-QUAT were used in this study. Zatosetron and zatosetron-QUAT showed high affinity and selectivity for 5-HT3 receptors in radioligand binding studies. Both compounds antagonized 5-HT-induced bradycardia in rats with an approximate ID50 of 0.7 and 0.2 microgram/kg i.v., respectively. Zatosetron and tropisetron significantly inhibited cisplatin-evoked emesis in dogs (estimated ID50 values of 34.4 +/- 2.3 micrograms/kg and 108.3 +/- 4.8 micrograms/kg i.v., respectively). Zatosetron-QUAT (0.01-1.0 mg/kg i.v.) had no effect. [14C]-zatosetron-QUAT (100 micrograms/kg) was not detected in the brain after i.v. administration to rats, consistent with the inability of charged compounds to achieve significant brain concentrations. However, i.c.v. administration (100 ng/kg) of zatosetron-QUAT reduced emetic episodes significantly (11.6 +/- 1.6 vs. 2.8 +/- 1.2). These studies suggest that, in dogs, antagonism of 5-HT3 receptors located within the blood-brain barrier is important to block cisplatin-induced emesis.

Topics: Animals; Benzofurans; Binding Sites; Blood-Brain Barrier; Bradycardia; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Cerebral Cortex; Cisplatin; Dogs; In Vitro Techniques; Male; Rats; Rats, Sprague-Dawley; Serotonin Antagonists; Vomiting

This report describes the development of novel benzamides which are orally active, highly potent, specific antagonists of 5-HT3 receptors. Described in this first report are the structure-activity relationships that led to novel structures with improved potency and selectivity. From this series of compounds, (S)-28 was identified and selected for further evaluation as a 5-HT3 receptor antagonist. Compared with 5-HT3 antagonists such as GR 38032F, BRL 43694, and metoclopramide, (S)-28 was most active in (a) inhibiting binding to 5-HT3 receptor binding sites in rat entorhinal cortex with an Ki value of 0.19 nM and (b) blocking cisplatin-induced emesis in the ferret with an ED50 value determined to be 9 micrograms/kg po.

Topics: Animals; Antiemetics; Benzamides; Benzofurans; Binding, Competitive; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Cerebral Cortex; Cisplatin; Ferrets; Granisetron; Imidazoles; Indazoles; Indoles; Male; Metoclopramide; Molecular Structure; Ondansetron; Rats; Receptors, Serotonin; Serotonin Antagonists; Structure-Activity Relationship; Vomiting

Two new classes of potent 5-HT3 agents have been developed and examined as inhibitors of cytotoxic drug induced emesis in the ferret and dog. The absolute configuration of the most active molecules 10 and 18 have been determined by X-ray crystallography. These two compounds are more potent than known 5-HT3 receptor antagonists both in vivo and in vitro in blocking 5-HT3 receptor activation and preventing chemotherapeutic induced emesis. Compared with 5-HT3 antagonists, such as GR 38032F, zacopride, BRL 43694, and ICS 205-930, compound 10 was more potent in (1) inhibiting binding to 5-HT3 receptor binding sites in rat cortex (Ki = 0.17 nM), (2) blocking the von Bezold-Jarisch effect in the rat (lowest effective dose, 1 microgram/kg iv), and (3) inhibiting 5-HT-induced contraction of guinea pig ileum (lowest effective concentration, 10(-9) M). This novel agent was as effective given po as when given iv in reducing cisplatin-induced emetic episodes in the ferret (ED50 = 4 micrograms/kg iv or po). A 1 mg/kg po dose of 10 virtually abolished cisplatin-induced emesis for 10 h in the ferret. However, it was inactive against apomorphine or copper sulfate-induced vomiting. These data, coupled with receptor binding studies of ligands for D2-dopamine, a1, a2, 5-HT1, 5-HT2, and muscarinic receptors demonstrate that 10 is a highly selective 5-HT3 receptor antagonist with remarkable potency in vivo.

Topics: Amides; Animals; Antiemetics; Benzamides; Benzofurans; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Cerebral Cortex; Cisplatin; Dogs; Ferrets; Guinea Pigs; Ileum; Molecular Structure; Muscle Contraction; Rats; Serotonin; Serotonin Antagonists; Structure-Activity Relationship; Vomiting; X-Ray Diffraction

RG 12915 [4-[N-(1-azabicyclo[2.2.2.]octan-3-(S)-yl)]2-chloro-cis 5a-(S)-9a-(S)-5a,6,7,8,9,9a-hexahydrobenzofurancarboxamide hydrochloride] is a potent and effective agent against cisplatin-induced emesis in the ferret after i.v. or p.o. administration. This agent (p.o.) is also highly protective against cisplatin-induced emesis in the dog, as well as cyclophosphamide/doxorubicin-induced emesis in the ferret. When administered either p.o. or i.v., RG 12915 has a lower ED50 value (0.004 mg/kg) than GR 38032F, BRL 43694 and metoclopramide for attenuating cisplatin-induced emetic episodes in the ferret. It also has a long duration of action against cisplatin-induced emesis in the ferret. In contrast to metoclopramide, RG 12915 lacks significant antidopaminergic activity both in vitro [( 3H]spiroperidol displacement), as well as in vivo (apomorphine-induced emesis). In radioligand binding assays, RG 12915 is a potent and selective displacer of binding of 5-hydroxytryptamine (5-HT)3 binding sites (IC50 value = 0.16 nM), whereas failing to displace binding of ligands for the alpha-1, alpha-2 and beta adrenergic, 5-HT1 or 5-HT2 or cholinergic-muscarinic sites with IC50 values less than 1 microM. At a p.o. dose (1 mg/kg) in which RG 12915 is highly protective against cisplatin-induced emesis in the dog, RG 12915 has no significant gastroprokinetic activity in the same species. In summary, RG 12915 is a potent and p.o. effective agent against cytotoxic drug-induced emesis in animal models. The antiemetic potency of RG 12915 against cisplatin is unrelated to antidopaminergic or gastroprokinetic activity, but may be related to its affinity for 5-HT3 binding sites.

Topics: Administration, Oral; Animals; Antiemetics; Antineoplastic Agents; Benzofurans; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Bridged-Ring Compounds; Cisplatin; Dogs; Dopamine; Ferrets; Gastric Emptying; Granisetron; Imidazoles; Indazoles; Ondansetron; Receptors, Serotonin; Serotonin Antagonists; Vomiting

Several 5-hydroxytryptamine (5-HT3) receptor antagonists have been described. In addition to 5-HT3 receptor antagonist activity, many of these agents also possess gastroprokinetic activity. In the present report, we identify compound LY277359 maleate as a potent, p.o. active, highly selective 5-HT3 receptor antagonist lacking gastroprokinetic effects. LY277359 maleate was a potent and selective antagonist of 2-methyl 5-HT-induced contraction in the guinea pig ileum (KB = 1.6 nM), a response mediated by activation of 5-HT3 receptors. Given both i.v. (0.0003, 0.001 and 0.003 mg/kg) and p.o. (0.01 and 0.03 mg/kg), LY277359 maleate inhibited the bradycardic response to i.v. administered 5-HT in urethane-anesthetized rats. The duration of antagonism of 5-HT-induced bradycardia persisted beyond 6 hr after p.o. administration of LY277359 maleate (0.03 mg/kg p.o.). In contrast to its potent 5-HT3 receptor antagonist activity, LY277359 maleate, in doses up to 1 mg/kg p.o., did not affect gastric emptying in rats, suggesting minimal, if any, gastroprokinetic activity of LY277359 maleate. This is in contrast to another 5-HT3 receptor antagonist, zacopride, which did produce a marked increase in gastric emptying in rats at doses of 0.1 mg/kg p.o. and higher. LY277359 maleate (0.03 and 0.1 mg/kg i.v. and 0.07, 0.1, 0.3 and 1.0 mg/kg p.o.) did have effects consistent with other 5-HT3 antagonists, to inhibit cisplatin-evoked emesis in dogs.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Benzofurans; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Bridged-Ring Compounds; Cisplatin; Dogs; Female; Gastric Emptying; Guinea Pigs; Heart Rate; In Vitro Techniques; Male; Muscle Contraction; Rats; Rats, Inbred Strains; Receptors, Serotonin; Serotonin; Serotonin Antagonists; Vomiting