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J M Cook

Publications and source records attributed to J M Cook.

At least 73 records · Page 4Linked to original sources
PubMed1987

Synthesis of 6-substituted beta-carbolines that behave as benzodiazepine receptor antagonists or inverse agonists.

The synthesis of the first beta-carboline, 6-(benzylamino)-beta-carboline (1c), to be devoid of a substituent at the 3-position and that still binds to benzodiazepine receptors with potent affinity is described. Furthermore, 1c proved to be a partial inverse agonist when tested in mice. Addition of the benzylamino group at the 6-position of the beta-carboline nucleus is primarily responsible for the activity of beta-carbolines 1b and 1c. The importance of the Nb-nitrogen atom for binding affinity was also demonstrated since 3-(benzylamino)carbazole (6) exhibited little or no affinity for benzodiazepine receptors in vitro, in contrast to the activity of 1c.

Animals↗
PubMed1987

Increased monocyte Fc-dependent chemiluminescence in renal transplant patients.

A luminol-enhanced chemiluminescence (CL) assay was used to study the microbicidal potential of phagocytic cells and the opsonic properties of serum in renal transplant recipients. Thirty-four patients receiving maintenance immunosuppression with prednisone and either cyclosporine or azathioprine and 35 normal controls were studied. Polymorphonuclear leukocytes (PMN) and monocytes were stimulated at the Fc receptor with heat-aggregated IgG (HAIgG) or immunoglobulin-treated zymosan (ITZ), and at the C3b receptor with serum-treated zymosan. Serum opsonic activity was determined by incubating zymosan with normal or patient serum and stimulating the CL response of normal phagocytes. We found that the Fc and C3b-dependent CL of PMN, the C3b-dependent CL of monocytes, and the opsonic properties of serum were identical in transplant recipients and normal controls. In contrast, the Fc-dependent CL of monocytes in renal transplant patients was 3 times greater than normal when stimulated with either soluble (HAIgG) or particulate (ITZ) ligands. These data suggest that some components of the host immune system are not affected by maintenance immunosuppressive medication in renal transplant recipients. The mechanisms and significance of the increased Fc-receptor-dependent CL observed in monocytes of renal transplant patients remain to be determined.

Azathioprine↗
PubMed1987

Premarital testing.

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HIV Seropositivity↗
PubMed1986

Anti-C3b-receptor (CR1) antibodies in patients with systemic lupus erythematosus.

Using an enzyme-linked immunoadsorbent assay, IgG in the plasma and purified IgG from 2 patients with systemic lupus erythematosus (SLE) were found to strongly react with purified C3b receptor (CR1) insolubilized on microtiter plates. The amount of IgG that bound to CR1 in 201 plasma samples from 179 other patients with SLE did not significantly differ from that which bound in 72 control samples from normal individuals. Purified IgG from the patients with anti-CR1 reactivity did not inhibit CR1 function in vitro. The number of CR1 antigenic sites expressed on erythrocytes from both patients was much lower than that observed in a normal population and in the lowest range of the decreased numbers found in patients with SLE. The occurrence of anti-CR1 antibodies in patients with SLE could provide an acquired mechanism for decreased expression of CR1 through antigenic modulation of the receptor on precursor cells and/or alter the function of cells of the immune system bearing C3b receptors.

Animals↗
PubMed1986

Differential antagonism of diazepam-induced loss of the righting response.

Ethyl-beta-carboline-3-carboxylate (beta-CCE), inosine and Ro 15-1788 are antagonists of several actions of the benzodiazepines. These compounds can be differentiated, however, according to their ability to reverse the loss of the righting response induced by diazepam. Ro 15-1788 completely reversed effects of diazepam on the righting response of pigeons and squirrel monkeys but was ineffective against comparable effects produced by pentobarbital. Pretreatment with Ro 15-1788 protected against diazepam-induced righting loss. Neither inosine nor beta-CCE reversed diazepam-induced righting loss or acted prophylactically against this effect. Since beta-CCE has been characterized as an inverse agonist at the benzodiazepine receptor, the absence of antagonism we report would suggest that beta-CCE lacks specific pharmacological activity which opposes suppression of the righting response by diazepam. Research with these preferentially-acting antagonists may lead to the development of anxiolytics devoid of the sedative-hypnotic properties inherent in the drugs currently in a clinical use.

Animals↗
PubMed1986

Cerebrovascular and cerebral metabolic effects of physostigmine, midazolam, and a benzodiazepine antagonist.

Physostigmine has been reported to reverse the sedation and paradoxical delirium induced by benzodiazepines. Little is known about how these drugs may interact to produce changes in cerebral metabolism and cerebral blood flow (CBF). In the present experiments, the effect of physostigmine on cerebral oxygen consumption (CMRO2) and CBF as well as the ability of physostigmine to reverse the effects of midazolam and 3-carbo-t-butoxy-B-carboline (B-CCT), a benzodiazepine antagonist, was tested in rats. Physostigmine by itself produced dose-dependent increases in blood pressure, CBF, and CMRO2, and it inhibited the decrease in these parameters produced by midazolam. Alone, B-CCT increased CBF and CMRO2, and these changes were potentiated by physostigmine. Thus, physostigmine increases CBF and CMRO2, probably by a direct effect on central cholinergic pathways. The ability of physostigmine to antagonize the metabolic effects of midazolam and to potentiate the stimulation produced by B-CCT suggests an additive effect of the two neurotransmitter systems rather than a direct interaction at the central receptor sites.

Anesthesia, Inhalation↗
PubMed1985

A benzodiazepine antagonist inhibits the cerebral metabolic and respiratory depressant effects of fentanyl.

It is reported that benzodiazepines such as diazepam will stimulate the opiate receptor system and that B-carboline drugs, which are benzodiazepine antagonists, may interact with opiate receptors directly. The ability of 3-hydroxymethyl-B-carboline (3-HMC) to antagonize several parameters of fentanyl anesthesia was tested here in rats. Fentanyl (25 and 100 micrograms/kg iv) produced dose dependent depression of cerebral blood flow (CBF), measured by radioactive microspheres, and cerebral oxygen consumption (CMRO2). These effects were significantly inhibited by 10 mg/kg 3-HMC iv. To test for the specificity of this effect, 3-HMC was also given to rats ventilated with inspire concentrations of 2% halothane. Halothane depressed CMRO2 equally in 3-HMC and vehicle treated rats, indicating no significant effect of the benzodiazepine antagonist. Blood pressure was increased in 3-HMC compared to vehicle treated animals during both fentanyl and halothane anesthesia. CBF was increased in 3-HMC vs vehicle treated rats during halothane anesthesia but this could be accounted for by the elevated blood pressure and lack of cerebral autoregulation rather than a direct cerebrovascular effect. 3-HMC decreased the sleep time and respiratory depressant effects of fentanyl but enhanced the analgesic effects of the opiate, as measured by time to respond to a hot plate stimulus. These results indicate that 3-HMC has the ability to specifically antagonize fentanyl anesthesia. These effects may be produced by an action of 3-HMC at the benzodiazepine receptor and/or by an action of the B-carboline at opioid receptors.

Anesthesia↗
PubMed1985

Interactions between the benzodiazepine receptor antagonist Ro 15-1788 (flumazepil) and the inverse agonist beta-CCE: behavioral studies with squirrel monkeys.

The effects of Ro 15-1788 and ethyl-beta-carboline-3-carboxylate (beta-CCE) were studied alone and in combination on the behavioral performances of squirrel monkeys. Under one procedure, performances maintained by food were suppressed by electric shock presentation (punishment or "conflict" procedure). Under a second procedure, responding was maintained either by food or electric shock delivery under a 5-min fixed-interval schedule. Doses of beta-CCE between 0.1 and 3.0 mg/kg, i.m., produced graded decreases in punished responding which were reversed by pretreatment with Ro 15-1788 (1.0 - 10.0 mg/kg, i.m.). Low doses of beta-CCE (0.03 - 0.3 mg/kg, i.m.) increased responding of monkeys maintained by shock presentation, but did not affect food-maintained responding; higher doses of beta-CCE decreased responding under both schedules. These effects of beta-CCE are opposite those produced by the benzodiazepines under this procedure. Ro 15-1788 (1.0 mg/kg i.m.) antagonized the effects of beta-CCE, producing a shift to the right in the dose-response curves. These findings provide further support for the view that beta-CCE and Ro 15-1788 produce effects mediated by the same benzodiazepine receptor recognition site.

Animals↗
PubMed1985

Evidence that a benzodiazepine receptor mechanism regulates the secretion of pituitary beta-endorphin in rats.

The effects of agents representing three classes of benzodiazepine receptor-acting drugs on circulating levels of beta-endorphin-like immunoreactivity (beta-END-LI) were examined in male rats. The active benzodiazepine receptor antagonists, ethyl-beta-carboline-3-carboxylate (beta-CCE, 30 mg/kg), methyl-beta-carboline-3-carboxylate (3 mg/kg), and 2-phenylpyrazolo [4,3-c]quinolin-3(5H)-one (CGS-8216, 3 mg/kg), all evoked 3- to 4-fold increases in plasma levels of beta-END-LI as compared to control values. The beta-CCE-induced rise in circulating beta-END-LI was significantly attenuated by pretreatment with the agonist diazepam (2.5 mg/kg) and the antagonist ethyl-8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo-[1,5-alpha] [1,4]benzodiazepine-3-carboxylate (Ro 15-1788, 10 mg/kg) but was unaltered by morphine (1 and 5 mg/kg). Ro 15-1788 also significantly attenuated the methyl-beta-carboline-3-carboxylate- and CGS-8216-induced release of pituitary beta-END-LI in vivo. Morphine (5 mg/kg) and diazepam (5 mg/kg) together, but neither alone, significantly reduced the rise in plasma beta-END-LI due to physical immobilization or foot shock. Pretreatment with dexamethasone (100 micrograms), an inhibitor of pituitary anterior lobe (AL) beta-END-LI secretion, completely prevented the plasma beta-END-LI increase due to beta-CCE. Chromatographic analysis of plasma beta-END-LI revealed that most of the beta-END-LI secreted in response to beta-CCE and CGS-8216 resembles beta-lipotropin (beta-LPH), a marker for beta-END-LI release from the AL, in molecular size. Results of in vitro studies indicate that the effects of the anxiogenic agents, beta-CCE and CGS-8216, on AL beta-END-LI release in vivo were not mediated by direct actions of these agents on the pituitary gland. Together, these findings suggest that an interaction exists between a benzodiazepine receptor mechanism(s) and regulation of hypothalamic corticotropin-releasing factor(s) which in turn controls beta-END-LI secretion from the AL of the rat pituitary gland.

Animals↗
PubMed1985

Midazolam-ethanol interactions and reversal with a benzodiazepine antagonist.

The purpose of these experiments was to analyze the cerebrovascular and cerebral metabolic effects of midazolam, a short-acting water-soluble benzodiazepine, and to investigate its interaction with alcohol in rats. A benzodiazepine antagonist, 3-carbo-t-butoxy-beta-carboline (beta-CCT), was used to test the role of the benzodiazepine receptor in midazolam-alcohol effects. Experiments were carried out under 70% N2O, 30% O2 anesthesia. Rats were tested with intraperitoneal injections of 0.75-5 mg/g ethanol, intravenous infusions of 0.57, 5.75 mg/kg midazolam, and 1.15 mg/kg beta-CCT separately and in combination. Cortical cerebral blood flow (CBF) was measured with radioactive microspheres, and cerebral oxygen consumption (CMRO2) was determined from cortical CBF and arterial-sagittal sinus blood samples 20 min after ethanol treatment and/or after a 15-min drug infusion. Alcohol alone produced dose-related increases in plasma ethanol concentrations but no depression in CMRO2 except at the highest dose (5 mg/g). Midazolam infusions alone decreased cortical CBF and CMRO2 35-40%, while 2.5 mg/g alcohol (which did not depress CMRO2 alone) combined with midazolam produced a 70% depression of cortical CBF and metabolism. An infusion of beta-CCT given alone increased CMRO2 alone and reversed the depression in both cortical CBF and CMRO2 produced by midazolam plus alcohol. These results indicate that the ability of alcohol to potentiate benzodiazepine-induced sedation is not simply an additive effect but may be related to the facilitation by alcohol of benzodiazepine receptor binding. The fact that beta-CCT reversed midazolam-ethanol-induced depression suggests that the effect may be mediated through the benzodiazepine receptor.

Anesthesia, Intravenous↗
PubMed1985

Evaluation of two distinctive beta-carbolines on serotonin binding in human platelets.

6-MeOTHBC binds to both high and low affinity receptors in human platelets. The beta-carboline is less active than chlorimipramine at the low affinity site, and it is weaker than methysergide, a known 5-HT antagonist, at the high affinity site. The other beta-carboline, B-CCE, is not active at either receptor in platelets. The data supports the view that platelets could be used as a limited model for studying 5-HT-ergic neurons.

Blood Platelets↗
PubMed1984

Cerebrovascular and cerebral metabolic effects of flurazepam and a benzodiazepine antagonist, 3-hydroxymethyl-beta-carboline.

There is a need in clinical practice for an antagonist which can reverse the sedative action of benzodiazepines. Recently, 3-hydroxymethyl-beta-carboline (3-HMC) has been reported to inhibit the sleep inducing effects of flurazepam. The effects of flurazepam (0.5, 5 and 50 mg/kg) on cerebral blood flow (CBF) and cerebral O2 consumption (CMRO2) were evaluated in rats and the ability of 3-HMC to reverse these changes was determined. Regional CBF was measured with radioactive microspheres and cortical CMRO2 was calculated from sagittal sinus-arterial O2 content differences and cortical CBF. Flurazepam produced dose dependent decreases in CBF and CMRO2 which were significant at 5 and 50 mg/kg. 3-HMC (5 mg/kg) inhibited flurazepam induced changes at the 5 mg/kg dose but had little effect on the CBF and CMRO2 depression produced by 50 mg/kg flurazepam. At a dose of 25 mg/kg, 3-HMC inhibited the effects of both 5 and 50 mg/kg flurazepam. Blood pressure and heart rate were also decreased by flurazepam but these variables were not reversed as effectively by 3-HMC treatment. The results indicate that 3-HMC is an active antagonist of the cerebrovascular and cerebral metabolic depression produced by flurazepam and can stimulate CBF and CMRO2 at high doses when given alone.

Animals↗
PubMed1984

beta-Carboline-3-carboxylate-t-butyl ester: a selective BZ1 benzodiazepine receptor antagonist.

The effectiveness of beta-carboline-3-carboxylate-t-butyl ester (beta CCtB) in antagonizing the anticonvulsant, ataxic and antipunishment effects of diazepam were evaluated. In mice, beta CCtB at doses of 3 and 10 mg/kg produced a dose-related antagonism of the anticonvulsant effects of diazepam against pentylenetetrazole (80 mg/kg). A dose of 30 mg/kg of beta CCtB did not produce a further shift in the diazepam dose-effect curve, apparently because beta CCtB failed to block the muscle-relaxant effects of diazepam. Further, beta CCtB (30 mg/kg) failed to antagonize the ataxic effects of diazepam in an inverted screen test. Rats responded under a multiple schedule where in one component every twentieth response (FR20) resulted in water presentation (unpunished component) and in another component every twentieth response (FR20) resulted in both shock and water presentation (punished component). Diazepam p.o. (0.1 to 10 mg/kg) first increased and then decreased rates in the punished component but only decreased rates in the unpunished component. beta CCtB had no effect on response rates when administered alone, but antagonized the rate-increasing effects of diazepam in the punished component. beta CCtB did not alter the rate-decreasing effects of diazepam in either component. Thus, beta CCtB selectively antagonized the effects of diazepam on punished behavior as well as the anticonvulsant effects of diazepam, but beta CCtB failed to antagonize the rate-decreasing and ataxic effects of diazepam. These results are consistent with the interpretation that beta CCtB is a selective BZ1 benzodiazepine receptor antagonist.

Animals↗
PubMed1984

Biomimetic approach to potential benzodiazepine receptor agonists and antagonists.

Several beta-carbolines, isoquinolines, imidazopyridines , and canthin -6-ones prepared in biomimetic fashion were tested for their ability to bind to the benzodiazepine receptor. Methyl isoquinoline-3-carboxylate, methyl 6,7- dimethoxyisoquinoline -3-carboxylate (3b) 1-phenyl-3- carbomethoxyimidazopyridine , (6B,) and canthin -6- one ( 13a ) bound with moderate affinities, while 2- carbomethoxycanthin -6- one ( 13b ) bound to benzodiazepine receptors with an affinity comparable to several pharmacologically active benzodiazepines. The potency of 13b suggests that the benzodiazepine receptor(s) can tolerate substitution at positions 1 and 9 of a beta-carboline without loss of activity if the substituents are trigonal and maintain a planar topography. Moreover, displacement of the carbonyl group by two atoms from the aromatic ring (C) of the beta-carboline skeleton caused a marked decrease in binding to the benzodiazepine receptor. This observation supports the hypothesis that maximum binding affinity of beta-carbolines is achieved when the carbonyl group at position 3 is attached directly to the aromatic pyridine ring.

Animals↗
PubMed1984

Structural features of the quinidine and quinine molecules necessary for binding of drug-induced antibodies to human platelets.

Although most quinidine- and quinine-induced platelet antibodies react only in the presence of the drug that provoked sensitization, some are active with either quinidine or its stereoisomer, quinine; that is, they are "cross-reactive." This suggests that the activity of drug-dependent antibodies is dependent on different structural features of the quinidine or quinine molecules. To investigate this possibility, we studied reactions of 16 quinidine- and quinine-induced antibodies with quinidine, quinine, and analogues of these drugs modified at the quinoline ring (desmethoxy-derivative), the quinuclidine ring (dihydro-derivative), or the asymmetric C(9)-hydroxyl position. It was found that the antibodies could be classified into three groups on the basis of their reactions with platelets in the presence of these compounds. Eight antibodies (group 1) reacted only in the presence of the sensitizing drug or its dihydro- or desmethoxy-derivative. Three antibodies (group 2) differed from those in group 1 only in that their reactions were markedly weakened when the primary desmethoxy-derivative was used. Five antibodies (group 3) reacted in the presence of the sensitizing drug, its stereoisomer, and one or more of the analogues tested, including at least one of the C(9)-derivatives. Antibodies in this group gave stronger reactions with the sensitizing drug than with its stereoisomer. These results provide further evidence for heterogeneity among drug-induced platelet antibodies by demonstrating that noncross-reactive antibodies (groups 1 and 2) are dependent for their activity on a specific configuration at the optically active C(9)-hydroxyl position, and that some of these (group 2) also require the methoxy group for full reactivity. In contrast, cross-reactive antibodies (group 3) appear to be dependent on the quinoline ring common to all the analogues tested but also require a specific configuration at C(9) for full reactivity.

Adult↗
PubMed1983

A benzodiazepine receptor antagonist decreases sleep and reverses the hypnotic actions of flurazepam.

The benzodiazepine receptor antagonist 3-hydroxymethyl-beta-carboline, which blocks several of the pharmacological actions of benzodiazepines, induces a dose-dependent increase in sleep latency in the rat. Furthermore, at a low dose that by itself does not affect sleep, 3-hydroxymethyl-beta-carboline blocks sleep induction by a large dose of flurazepam. The benzodiazepine receptor may play a role in both the physiological regulation and pharmacological induction of sleep.

Animals↗