benzofurans and zatosetron

The superfamily of heme-thiolate proteins known as the cytochromes P450 is responsible for the oxidative metabolism of the majority of drugs. Thus, the phenotypes of individuals with respect to their levels of catalytically active cytochromes P450 determines to a large part the substantial interindividual variation observed in the metabolic clearance of drugs. Over the past 10 years 15 different human cytochromes P450 involved in drug metabolism have been isolated and characterized to varying degrees. This brief review discusses the characterization of these cytochromes P450 and how this knowledge has been used by the pharmaceutical industry to aid in the development of new drugs.

Topics: Benzofurans; Bridged Bicyclo Compounds, Heterocyclic; Cytochrome P-450 Enzyme System; Drug Design; Enzyme Induction; Genetic Variation; Humans; In Vitro Techniques; Liver; Metabolic Clearance Rate; Microsomes, Liver; Pharmaceutical Preparations; Phenotype; Serotonin Antagonists

The aim of this study was to make a preliminary investigation of the efficacy and safety of zatosetron maleate, a selective 5-hydroxytryptamine-3 receptor antagonist for patients with a broad range of anxiety symptoms. A double-blind, parallel, placebo-controlled pilot study was conducted in 43 patients, aged 18 to 65 years, scoring >17 on the Hamilton Rating Scale for Anxiety (HAM-A). Patients were randomly assigned to either a fixed oral dose of 0.2, 1, or 5 mg of zatosetron or placebo for 4 weeks, followed by a 2-week placebo phase. Enhanced blinding procedures reduced the influence of side effects on efficacy ratings and obscured phases of the research design to patient and clinician. A change in HAM-A scores from baseline to endpoint was the principal efficacy measure; HAM-A Psychic and Somatic subscales, the Symptom Checklist-90, Montgomery-Asberg Depression Rating Scale, and Clinical Global Impressions Scale subscales provided secondary change indices. Adverse events (AEs) (spontaneously mentioned and elicited with the Udvalg for Kliniske Undersøgelser side effect rating scale), vital signs, electrocardiographic findings, and laboratory analytes were compared among treatment groups. Eighty-eight percent of the patients met the criteria for generalized anxiety disorder. No statistically significant differences in outcome measures differentiated among the four treatment groups. However, a pattern of greater change in the HAM-A scores seemed to favor zatosetron over placebo. Placebo was associated with only modest HAM-A score changes and a 30% response rate. The greatest numeric decrease in the HAM-A score and the highest response rate (45%) occurred in the groups receiving 0.2 and 1 mg of zatosetron. The secondary measures of efficacy demonstrated similar outcomes. There were no deaths or serious AEs reported in this study. This pilot study demonstrated that zatosetron at doses of 0.2 to 5 mg/day was safe. Although statistical significance was not achieved, the results show a greater numeric trend toward reducing anxiety with zatosetron than with placebo.

Topics: Adult; Anxiety Disorders; Benzofurans; Bridged Bicyclo Compounds, Heterocyclic; Double-Blind Method; Female; Humans; Male; Middle Aged; Pilot Projects; Psychiatric Status Rating Scales; Serotonin Antagonists

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

Previous studies have suggested that the alpha2-adrenergic receptor antagonist yohimbine produced antinociceptive effects in the formalin test in rats. However, yohimbine is also an agonist at serotonin (5-HT)1A receptors, suggesting the possibility that the antinociceptive effects of yohimbine might be mediated via these receptors.. The purpose of the present studies was to evaluate the potential role of 5-HT(1A) receptors in mediating the antinociceptive effects of yohimbine.. The antinociceptive effects of yohimbine were evaluated using the formalin test in rats.. Yohimbine (2.5-10 mg/kg s.c.) produced dose-related antinociception during both phase I and phase II of the formalin test, and was approximately equipotent and equiefficacious to morphine. The selective 5-HT(1A) receptor antagonist WAY 100,635 (0.03-3.0 mg/kg s.c.) produced a partial reversal of yohimbine. In comparison, the selective 5-HT(1A) receptor agonist (+/-)8-hydroxy-dipropylaminotetralin HBr (8OH-DPAT; 1.0 mg/kg s.c.) also produced a dose-related antinociception in the formalin test, although 8OH-DPAT was completely reversed by WAY 100,635 (3.0 mg/kg s.c.). The antinociceptive effects of yohimbine were not antagonized by the 5-HT(1B/1D) antagonist GR 127935 (1.0 mg/kg and 3.0 mg/kg s.c.), the 5-HT2 antagonist LY53857 (1.0 mg/kg s.c.), or the 5-HT3 antagonist zatosetron (3.0 mg/kg s.c.).. The present results demonstrate that yohimbine produces a dose-related antinociception in the formalin test in rats which is mediated in part by the agonistic actions at 5-HT(1A) receptors.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Adrenergic alpha-Antagonists; Animals; Benzofurans; Bridged Bicyclo Compounds, Heterocyclic; Dose-Response Relationship, Drug; Ergolines; Formaldehyde; Male; Nociceptors; Oxadiazoles; Pain; Pain Measurement; Piperazines; Pyridines; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT1D; Receptors, Serotonin; Receptors, Serotonin, 5-HT1; Serotonin Antagonists; Serotonin Receptor Agonists; Time Factors; Yohimbine

Topics: Animals; Anti-Anxiety Agents; Antiemetics; Anxiety Disorders; Benzofurans; Bridged Bicyclo Compounds, Heterocyclic; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Humans; Rats; Receptors, Serotonin; Receptors, Serotonin, 5-HT3; Serotonin Antagonists

Topics: Adult; Animals; Benzofurans; Bridged Bicyclo Compounds, Heterocyclic; Clinical Trials, Phase II as Topic; Half-Life; Humans; Male; Migraine Disorders; Serotonin Antagonists

Specific binding of [3H]strychnine was studied on membranes prepared from rat spinal cord. Several antagonists and agonists of 5-HT3 receptors and tropane derivatives displaced [3H]strychnine binding with micromolar potencies. In the presence of 10 microM glycine a high affinity (nanomolar) component of displacement was also observed for the tropeines zatosetron, bemesetron and tropisetron. The displacing potency of glycine was also enhanced by these agents which are therefore termed glycine-positive. In contrast, atropine, SR 57227A, m-chlorophenylbiguanide, metoclopramide and granisetron are termed glycine-negative, because they decreased the displacing potency of glycine while glycine decreased the displacing potencies of atropine and metoclopramide. The dissociation of [3H]strychnine binding was accelerated in the presence of m-chlorophenylbiguanide, SR 57227A, atropine and zatosetron with a concentration dependence (EC50 values and Hill slopes) similar to their displacing effects. This demonstrates that the displacement of strychnine binding is associated with allosteric interactions between different binding sites. Structure-activity analysis revealed that the tropeine structure is essential for high affinity binding, and its substitutions (in scopolamine and cocaine) or its replacement (in ondansetron and metoclopramide) strongly decrease the potency and/or efficacy of allosteric modulation. High affinity modulatory sites for tropeines appear to be associated with the potentiation of ionophore function, but distinct from the low affinity channel blocking sites as well as from the binding sites of strychnine and glycine.

Topics: Allosteric Regulation; Animals; Benzofurans; Binding, Competitive; Bridged Bicyclo Compounds, Heterocyclic; Glycine; Granisetron; Indoles; Ligands; Male; Medulla Oblongata; Ondansetron; Pons; Rats; Rats, Wistar; Receptors, Glycine; Receptors, Serotonin; Receptors, Serotonin, 5-HT3; Serotonin Antagonists; Serotonin Receptor Agonists; Spinal Cord; Strychnine; Tropanes; Tropisetron; Tubocurarine

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

A 1-year chronic toxicity study was conducted in which rhesus monkeys (4/sex/dose) were given daily doses of 0, 3, 10, or 25 mg zatosetron/kg by nasogastric intubation. Clinical signs of toxicity characterized by salivation, diarrhea or soft stools, and/or emesis occurred in animals that received 10 or 25 mg/kg of zatosetron. One monkey in the high-dose group and one in the middle-dose group died as a result of intratracheal administration of the compound. The death of another monkey in the high-dose group was associated with an unexpectedly high (3-fold the mean plasma Cmax value in surviving females in this group) plasma level of zatosetron as indicated by postmortem analysis of heart blood. Animals of both sexes in all treatment groups gained weight at a slightly reduced rate when compared to control monkeys. Depressed appetite occurred in some monkeys in all treatment groups but was most evident in those receiving 25 mg/kg. Evaluation of ECG's indicated that treatment with zatosetron did not produce any rhythm or conduction disturbances. However, there was a mild increase in the Q-Tc interval throughout the treatment period at 4 hours postdosing in monkeys in the middle- and high-dose groups and a slight increase prior to dosing in animals in the high-dose group. Mean plasma Cmax and AUC(0-24 hr) values on Day 360 were dose proportional for zatosetron and for the N-demethylated metabolite in both sexes over the dose range tested. The mean t1/2 (elimination phase) for the plasma disappearance of zatosetron ranged from 3.4 to 7.2 hr in males and from 2.3 to 6.8 hr in females. Hematology, urinalysis, and clinical chemistry parameters were unaffected by treatment. There were no treatment-related gross or microscopic alterations or changes in organ weights. With the exception of mild effects on body weight gain, there was no evidence of chronic toxicity in monkeys given 3 mg/kg zatosetron daily for 1 year.

Topics: Animals; Appetite; Benzofurans; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Dose-Response Relationship, Drug; Electrocardiography; Female; Macaca mulatta; Male; Serotonin Antagonists; Weight Gain

The 5-HT3-receptor antagonist, ondansetron, has been shown to have positive effects in selected in-vivo models of memory impairment and anxiety. The exact mechanisms underlying such bioactivities are unknown. In the present work, an 86Rb efflux bioassay was used to show that ondansetron has a unique ability to block voltage-gated potassium channels in TE671 human neuroblastoma cells. This intrinsic potassium-channel-blocking (KCB) property is relatively weak (IC50 20 microM), but is not shared by other 5-HT3-receptor ligands including zatosetron, MDL 72222, LY 278, 584, zacopride, 1-phenylbiguanide, and ICS 205-930 (tropisetron). Pre-incubation of the target neuroblastoma cells with several 5-HT-receptor ligands including 5-hydroxytryptamine, 8-OH-DPAT, ketanserin, 2-methyl-5-HT, as well as a number of potent 5-HT3 agonists and antagonists and two selective neurotoxins, failed to abolish the KCB action of ondansetron. A preliminary structure-activity relationship analysis indicates that the KCB activity of ondansetron is almost entirely attributable to its structural nucleus, 2,3-dihyro-9-methyl-4(1H)-carbazolone. It is hypothesized that the KCB action of ondansetron is mediated through receptors other than 5-HT3 receptors. The KCB activity of ondansetron may be a significant factor in the in-vivo cognition-enhancing activities of this compound, conceivably due to depolarization of the hippocampal synaptic membranes and a consequent augmentation of neurotransmission.

Topics: Anti-Anxiety Agents; Benzamides; Benzofurans; Biguanides; Bridged Bicyclo Compounds, Heterocyclic; Humans; Hypoglycemic Agents; Indazoles; Indoles; Neuroblastoma; Neurotoxins; Ondansetron; Potassium Channels; Receptors, Serotonin; Receptors, Serotonin, 5-HT3; Rubidium Radioisotopes; Serotonin Antagonists; Serotonin Receptor Agonists; Structure-Activity Relationship; Tropanes; Tropisetron; Tumor Cells, Cultured

Micturition was evoked in conscious cats by infusing saline into the bladder at a physiological rate. Drugs were administered intrathecally. Micturition volume threshold was increased by 5-hydroxytryptamine (5-HT, serotonin) and decreased by zatosetron, a 5-HT3 receptor antagonist, in spinally intact cats. Thus 5-HT3 receptors inhibit micturition. After complete spinal transection, serotonin reduced volume threshold in 3 of 4 cats, indicating an alteration in serotonergic control. However, 2-methyl-5-HT, a 5-HT3 receptor agonist, increased volume threshold. Thus 5-HT3 receptor-mediated inhibition of bladder function remains after spinal transection. We conclude that some, but not all, serotonergic modulation of bladder function is altered after spinal transection.

Topics: Animals; Benzofurans; Bridged Bicyclo Compounds, Heterocyclic; Cats; Dose-Response Relationship, Drug; Male; Serotonin; Spinal Cord; Spinal Cord Injuries; Time Factors; Urinary Bladder; Urination

Studies were done to characterize the chronic toxicity, metabolism, and pharmacokinetics of a 5-HT3 receptor antagonist in Fischer 344 rats. Animal were given daily gavage doses of 10, 30, or 90 (females only were increased from 90 to 120 mg/kg for months 7-12) mg/kg of zatosetron for 1 year. Treatment-related histologic changes occurred primarily in the liver and kidney of rats given 30 or 90/120 mg/kg and consisted of hepatocellular fatty change (males only), hepatic granuloma formation, and histiocytosis (females only), and renal pigment deposition (both sexes), lesions not previously described in animals treated with 5-HT3 receptor antagonists. Decreased erythrocyte parameters, increased total leukocyte, lymphocyte, and neutrophil counts, and increased serum alkaline phosphatase, gamma glutamyltransferase, alanine transaminase, and liver weights in females were most likely related to the chronic inflammatory process in the liver. Increased alanine transaminase and transiently increased alkaline phosphatase with increased liver weights in males were likely related to the hepatocellular fatty change. Increased renal tubular epithelial pigment deposition (lipofuscin and hemosiderin) was observed in males and females in the high-dose group and in females in the middle-dose group. Both had increased kidney weights and increased serum inorganic phosphorus. Females in the high-dose group had increased urine volume, decreased pH, and increased total excretion of sodium, potassium, chloride, and creatinine. These changes may have been a reflection of tubular dysfunction associated with excessive pigment deposition. No toxicologically significant effects occurred in rats treated with 10 mg/kg/day for 1 year. Plasma concentrations of zatosetron and its 3-hydroxy metabolite increased with increasing dose and duration of dosing in both males and females during the first 6 months of dosing. Subsequent values measured at 12 months showed no substantive increases except in males given the highest dose. At comparable doses, consistent sex differences (F > M) in mean 1-hr plasma content of parent compound were evident across dose and time. Zatosetron-induced hepato- and nephrotoxicity seems to be peculiar to the rat and is observed only at very high doses relative to the proposed human clinical dose.

Topics: Animals; Benzofurans; Blood; Blood Cells; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Female; Hydroxylation; Kidney; Liver; Male; Organ Size; Rats; Rats, Inbred F344; Serotonin Antagonists

Antagonists of 5HT3 receptors are clinically effective in treating nausea and emesis associated with certain oncolytic drugs, including cisplatin. Moreover, these agents may be useful in pharmacological management of several central nervous system disorders, including anxiety, schizophrenia, dementia, and substance abuse. Our studies on aroyltropanamides led to the discovery that dihydrobenzofuranyl esters and amides are potent 5HT3 receptor antagonists. Simple benzoyl derivatives of tropine and 3 alpha-aminotropane possessed weak 5HT3 receptor antagonist activity, as judged by blockade of bradycardia produced by iv injection of serotonin (5HT) to anesthetized rats. Within this series, use of benzofuran-7-carboxamide as the aroyl moiety led to a substantial increase of 5HT3 receptor affinity. The optimal 5HT3 receptor antagonist identified via extensive SAR studies was endo-5-chloro-2,3-dihydro-2,2-dimethyl-N-(8-methyl-8-azabicyclo[3.2.1]oc t- 3-yl)-7-benzofurancarboxamide (Z)-2-butenedioate (zatosetron maleate). The 7-carbamyl regiochemistry, dimethyl substitution, chloro substituent, and endo stereochemistry were all crucial elements of the SAR. Zatosetron maleate was a potent antagonist of 5HT-induced bradycardia in rats (ED50 = 0.86 micrograms/kg i.v.). Low oral doses of zatosetron (30 micrograms/kg) produced long-lasting antagonism of 5HT3 receptors, as evidenced by blockade of 5HT-induced bradycardia for longer than 6 h in rats. Moreover, this compound did not produce hemodynamic effects after i.v. administration to rats, nor did it block carbamylcholine-induced bradycardia in doses that markedly blocked 5HT3 receptors. Thus, zatosetron is a potent, selective, orally effective 5HT3 receptor antagonist with a long duration of action in rats.

Topics: Animals; Benzofurans; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Guinea Pigs; Heart Rate; In Vitro Techniques; Indoles; Male; Muscle Contraction; Muscle, Smooth; Rats; Rats, Inbred Strains; Serotonin Antagonists; Structure-Activity Relationship; Tropisetron

In this study, we examined the effect of the 5-HT3 receptor antagonists LY 277359 and granisetron on the suppressant action of the dopamine receptor agonist (+/-)-apomorphine on spontaneously active dopamine cells in the substantia nigra pars compacta (SNC or A9) and ventral tegmentum area (VTA or A10) in the rat. This was accomplished using the standard extracellular single unit recording techniques. The i.v. administration of (+/-)-apomorphine (1-64 micrograms/kg) produced a dose-dependent suppression of the basal firing rate of spontaneously active A9 and A10 dopamine cells. The i.v. administration of LY 277359 at 0.01 and 0.1 mg/kg, but not 1 or 10 mg/kg, potentiated the suppressant action of (+/-)-apomorphine on A10 dopamine cell firing. In contrast, (+/-)-apomorphine's suppressant action on the firing rate of A10 dopamine neurons was potentiated by all doses of granisetron except the 10 mg/kg dose. The suppressant action of (+/-)-apomorphine in control and pretreated rats was reversed by the i.v. administration of haloperidol (0.05-0.1 mg/kg). In contrast, the suppression action of (+/-)-apomorphine on the firing rate of A9 dopamine cells was not altered by any dose of LY 277359 or granisetron. Overall, our results suggest that LY 277359 and granisetron selectively potentiate the response of A10 dopamine cells to (+/-)-apomorphine.

Topics: Animals; Apomorphine; Benzofurans; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Dopamine; Drug Synergism; Granisetron; Indazoles; Male; Microelectrodes; Neurons; Rats; Rats, Inbred Strains; Serotonin Antagonists; Stereotaxic Techniques; Substantia Nigra; Tegmentum Mesencephali

Compound LY277359 maleate undergoes a photoinduced solvolysis reaction in water to generate the corresponding hydroxylated product and release chloride. Attempts to stabilize a parenteral formulation of the compound led to an investigation of possible reaction mechanisms. The data are consistent with a mechanism involving homolytic cleavage of the aryl-chloride bond followed by electron transfer to give an aryl cation intermediate. The cation thus formed reacts with surrounding nucleophiles to give the substituted product. A kinetic expression for reaction rate was derived from the mechanism, and various components of the rate constant were evaluated experimentally. The reaction is slowed with the addition of chloride, presumably via a common ion effect (enhanced retroreaction). In the absence of added chloride, the reaction can be described kinetically by an initiation term. An inner filter effect is also observed, where increasing amounts of the hydroxylated product slow the reaction. Experimental data for observed rate constants as a function of starting concentration and light intensity are fit with good correlation to an equation describing the filter effect. Additional studies evaluated the effects of various structural features of the parent compound on the rate of the reaction in glass containers. It was determined that reactivity was dependent on two features: (1) the ortho positioning of the carboxyl and ether groups, which shifted an absorption band above the container cutoff; and (2) the para orientation of the chloro group to the ether, which is para activating in the photoexcited state.

Topics: Benzofurans; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Chromatography, High Pressure Liquid; Kinetics; Molecular Structure; Photochemistry; Serotonin Antagonists; Spectrophotometry, Ultraviolet; Structure-Activity Relationship

In this study, we have examined the effect of acute and chronic administration of LY 277359, a putative 5-HT3 receptor antagonist, on the number of spontaneously active dopamine cells in the substantia nigra pars compacta (SNC or A9) and ventral tegmental area (VTA or A10). This was accomplished using the standard extracellular single unit recording techniques. The acute administration of LY 277359 (0.1 or 1.0 mg/kg i.p.) produced a significant increase in the number of spontaneously active A10, but not A9, dopamine cells compared to saline controls. The acute administration of 10 mg/kg of LY 277359 did not significantly alter the number of spontaneously active dopamine cells in either area. In contrast to its acute effects, the administration of 0.1 mg/kg per day of LY 277359 for 21 days decreased the number of spontaneously active A9 and A10 dopamine cells. However, the i.v. administration of (+/-)-apomorphine (50 micrograms/kg) did not reverse LY 277359's action, suggesting that the chronic LY 277359-induced reduction of dopamine cells was not the result of depolarization block. To test whether chronic administration of LY 277359 at a high dose would induce depolarization block of dopamine cells, rats were treated with 1.0 or 10 mg/kg LY 277359. Interestingly, the chronic administration of 1.0 mg/kg LY 277359 increased the number of A10, but not A9 dopamine cells. In contrast, chronic treatment with 10 mg/kg selectively decreased the number of spontaneously active A10 dopamine cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Benzofurans; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Dopamine; Male; Mesencephalon; Neurons; Rats; Rats, Inbred Strains; Serotonin Antagonists; Substantia Nigra

Acute and chronic administration of low doses (e.g. 0.1, 0.3 mg/kg i.p.) of the selective 5-HT3 antagonist zatosetron decreased the number of spontaneously active A 10 dopamine cells but did not change the number of spontaneously active A9 dopamine cells; higher doses (1.0, 10 mg/kg) were less effective. The decrease in the number of spontaneously active A 10 dopamine cells following zatosetron administration was not reversed by the administration of apomorphine. These data indicate that zatosetron's effects on spontaneously active dopamine neurons: (1) differs from other 5-HT3 antagonists; (2) may not be mediated by depolarization inactivation; and, (3) may be predictive of an atypical antipsychotic action without delayed onset.

Topics: Action Potentials; Animals; Apomorphine; Benzofurans; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Cell Count; Dopamine; Haloperidol; Male; Neurons; Rats; Rats, Inbred Strains

The potential of the investigational 5-hydroxytryptamine (5HT3) antagonist, LY277359, to alter cardiovascular, central nervous system (CNS), smooth muscle, and gastrointestinal functions at multiples of pharmacologically active doses, was examined to provide a profile of possible secondary pharmacological effects. In the anesthetized dog, significant cardiovascular effects were observed at doses 100-1000 and 4-15 times those found to be pharmacologically active at 5HT3 receptors in vivo in rats and dogs, respectively. These effects were limited to decreased heart rate (approximately 20%) at intravenous doses of 1.75 and 3.5 mg/kg and prolonged Q-Tc intervals (approximately 20 to 50%) at doses of 0.438 to 3.5 mg/kg. At an oral dose of 135 mg/kg (representing 1500-4500 times the pharmacologically active dose in rats), LY277359 induced hypoactive behavior and reduced body temperature in mice. Seizure activity was potentiated at high oral doses of LY277359 (45 and 135 mg/kg). A single oral dose of 135 mg/kg increased hexobarbital-induced sleep time. In smooth and cardiac muscle tissue studies in vitro, LY277359 was essentially inactive: it did not alter contractile activity or receptor function of the guinea pig ileum, rat vas deferens, rat uterus, or guinea pig atria at concentrations of 10(-5) to 10(-10) mol/l. At a concentration 50,000 times the 5HT3 antagonistic level in vitro (10(-4) mol/l), LY277359 inhibited the response of the ileum to field stimulation, acetylcholine and angiotensin I, and suppressed the rate of the spontaneously beating guinea pig atria in a noncompetitive manner.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Behavior, Animal; Benzofurans; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Central Nervous System; Digestive System; Dogs; Female; Guinea Pigs; Hemodynamics; In Vitro Techniques; Male; Mice; Muscle Contraction; Muscle, Smooth; Muscle, Smooth, Vascular; Rats; Serotonin Antagonists

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