The action of seven convulsants as antagonists of the GABA response of Limulus neurons.
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Animals↗
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Results for “Bridged Bicyclo Compounds”
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7-Aza analogs of the analgetic agent azabicyclane. Synthesis and pharmacologic analysis.
Three 3,7-diazabicyclo[3.3.1]nonane derivatives (4) with a structural similarity to the analgetic agent azabicyclane (1) were prepared. The amino alcohol 4a was found to prefer a conformation wherein the six-membered ring to which the hydroxyl group is syn is in the boat form. These three compounds had increased basicity in comparison with 1 due to various forces stabilizing their monocationic states. Compounds 4a-c did not show analgetic activity at the dose levels tested.
Analgesics↗
Cognitive enhancing actions of DuP 753 detected in a mouse habituation paradigm.
The potential of DuP 753, an angiotensin II receptor antagonist, to improve cognitive performance was assessed in a mouse habituation paradigm. On repeated daily testing DuP 753 (10.0 ng kg-1 p.o.) enhanced the basal cognitive performance of mice (decrease in latency to move from the light to the dark compartment and increases in the rears, line crossings and percentage of time spent in the dark compartment) and overcame the cognitive impairment induced by the administration of scopolamine (0.25 mg kg-1 i.p.). These findings further implicate the modulation of mental function by angiotensin II.
Angiotensin II↗
Thromboxane stimulates synthesis of extracellular matrix proteins in vitro.
The vasoconstrictor eicosanoid thromboxane plays an important role in the pathogenesis of several renal diseases. As an autacoid, its local release alters blood flow and induces platelet aggregation. We report a direct stimulatory effect of thromboxane on extracellular matrix protein production and gene expression in vitro. Treatment of two cell types, differentiated mouse teratocarcinoma cells (F9+) and human glomerular mesangial cells, with two different thromboxane analogues resulted in increased production of components of the extracellular matrix including fibronectin and the basement membrane proteins laminin and type IV collagen. These responses to thromboxane were not the result of a mitogenic effect of thromboxane nor the result of an increase in total cellular protein. The increased production of extracellular matrix proteins was, at least in part, due to an increase in the steady-state level of mRNA for these genes. Furthermore, the effect of thromboxane was markedly inhibited by cotreatment with a thromboxane-receptor antagonist. These results suggest a new potential role for thromboxane as a mediator of the sclerotic and fibrotic responses to injury.
15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
Thromboxane binding and signal transduction in rat glomerular mesangial cells.
Thromboxane A2 (TxA2) stimulates contraction of glomerular mesangial cells. However, mesangial cell TxA2 receptors have not been previously characterized. We therefore investigated TxA2 binding and TxA2-associated signal transduction pathways in rat glomerular mesangial cells using the specific thromboxane receptor agonist (1S-[1 alpha,2 beta(5Z),3 alpha-(1E,3S)4 alpha])-7-(3-[3-hydroxy-4-(p- iodophenoxy)-1-butenyl]7-oxabicyclo[2.2.1]hept-2-yl)-5-heptenoic acid (IBOP). In these cells, [125I]BOP binding was saturable, displaceable, and of high affinity. Scatchard analysis revealed a single class of binding sites with a dissociation constant (Kd) of 293 pM and a maximal density of binding sites (Bmax) of 33 fmol/mg protein. Specific binding was inhibited by the thromboxane agonist (15S)-hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5Z,13E-dienoic acid (U-46619) [inhibitor dissociation constant (Ki) = 297 nM] and the TxA2 receptor antagonists SQ 29548 (Ki = 1 nM) and (1R-[1 alpha(Z),2 beta,3 beta,5 alpha])-(+)-7-(5-[(1,1'-biphenyl)- 4-yl-methoxy]-3-hydroxy-2-(1-piperidinyl)cyclopentyl]-4-heptenoic acid (GR 32191) (Ki = 92 nM). Binding was also highly specific for thromboxane because prostaglandin E2 (Ki = 16 microM) and the inactive thromboxane metabolite, TxB2 (Ki = 41 microM), were approximately 1,000-fold less potent at inhibiting binding. IBOP stimulated phosphatidylinositol hydrolysis with an effective concentration of drug that produces 50% of the maximal response of 229 pM, which correlated well with the equilibrium Kd and enhanced phosphorylation of an acidic 80-kDa protein substrate for protein kinase C.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
[CNS-active 4-phenylpyranes: 9-phenyl-9-piperidino-3-oxa-7-azabicyclo[3.3.1]nonane].
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Analgesics↗
Derivatives of 5,7,7-trimethyl-6-oxa-3-azabicyclo [3.2.2] nonane with antiarrhythmic, local anesthetic and hypotensive activities. II.
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Acetylcholine↗
Interaction of bimane-labeled fluorescent tubulin with the isolated mitotic apparatus.
Fluorescent derivatives of cellular proteins that retain their native characteristics have become useful probes to investigate the dynamics of specific cytoskeletal proteins. In the experiments reported here, a previously characterized fluorescent derivative of tubulin, bimane-tubulin [Wadsworth and Sloboda, 1982a], was used to investigate microtubule assembly in vitro. The results demonstrate that bimane-tubulin was competent to assemble onto a variety of organizing centers in vitro, including microtubule organizing centers (MTOCs) present in homogenates of sea urchin eggs, isolated mitotic apparatuses (MAs), and lysed mitotic cells. When homogenates of fertilized sea urchin eggs containing MTOCs were incubated with bimane-tubulin at 37 degrees C, discrete areas of linear fluorescence were observed. Only diffuse fluorescence was observed when calcium or colchicine was added to the homogenate or if the temperature was maintained at 0 degrees C. Negative-stain electron microscopy of the fluorescent arrays revealed morphologically normal microtubules radiating from electron dense regions. When mitotic spindles, isolated in glycerol containing buffers and therefore cold stable, were incubated with bimane-tubulin, linear fluorescence was observed emanating from the spindle poles but not from the region occupied by the kinetochores. MAs incubated with bimane-labeled bovine serum albumin or bimane-labeled microtubule-associated proteins showed only diffuse fluorescence. However, when mitotic cells which were hypotonically lysed in the absence of detergents or microtubule stabilizing solvents, were perfused with bimane-tubulin intense fluorescence was observed in the asters and throughout the spindle. Two experiments suggested that the fluorescence observed in the results outlined above was due to the assembly of normal microtubules from the fluorescent subunits. First, the observed fluorescence was sensitive to cold temperature, which is known to disassemble microtubules. Second, when the isolated, fluorescent MAs were examined by thin section electron microscopy, microtubules of normal diameter were seen. No aggregated material appeared associated with the walls of the microtubules, which might have been expected if the fluorescent protein was nonspecifically adsorbed to the microtubules. The results of these experiments demonstrate that isolated, stabilized MAs support the growth of new microtubules from the spindle poles while labile spindles, present in lysed cells, incorporate fluorescent tubulin throughout the spindle and asters.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗
Synthesis and bronchodilator activity of endo-2-(2-cyclopentyl-2-hydroxy-2-phenyl)acetoxy-7-methyl-7- azabicyclo-[2.2.1]heptane methobromide, a potent and long-acting anticholinergic agent.
The synthesis of the alpha-cyclopentylmandelate ester of quaternized endo-7-methyl-7-azabicyclo[2.2.1]heptan-2-ol (4, RS-11635) is described. The key step of this synthesis consists of the intramolecular trans-diaxial epoxide opening of 4-(N-methylamino)-1,2-epoxycyclohexane (8) to form the endo-azabicyclic structure 9. Evaluation of anticholinergic bronchodilator activity by intravenous administration in methacholine-challenged guinea pigs indicated 4 to be approximately twice as potent as ipratropium bromide (ED50 of 1.1 versus 2 micrograms/kg) and to have a duration of action nearly five times as long (230 versus 50 min). Evaluation of anticholinergic bronchodilator activity by aerosol administration in methacholine-challenged dogs also indicated 4 to be approximately twice as potent as ipratropium bromide and to have a duration of action nearly three times as long.
Animals↗
Short-term studies with the cryptating agent hexaoxa-diaza-bicyclo-hexacosane in rats.
In short-term experiments rats received single doses of 50, 100, and 500 mumoles/kg of the cryptating agent A 222. A dose-related increase in the activities of GOT and GPT in the serum was observed 6 h after treatment, reaching values up to eleven and three times that of the controls, respectively. However, the enzyme activities returned to the control levels within 3 days. The activity of alkaline phosphatase and the levels of protein and cholesterol in serum were not altered during the observation period of 7 days. Histopathological examinations did not show any changes in the liver, kidney, heart, lung, thymus, spleen, or intestine. The elevations of GOT and GPT seem to be due to a transient liver lesion, since no histopathological alterations of the liver became apparent. These results show, that after single applications of A 222 at all doses used, no severe lesions occur in the observed organs.
Alanine Transaminase↗
The selective dopamine antagonist properties of BRL 34778: a novel substituted benzamide.
BRL 34778, exo-4-amino-5-chloro-2-methoxy-N-[9-(4-fluorophenylmethyl)-9-azabi cyclo(3.3.1) non-3-yl]-benzamide, is a very potent and specific dopamine D2-receptor antagonist. It exhibits a Ki value of 2.14 nM for dopamine D2-receptors but much lower affinity for D1-(Ki 5700 nM) and for many other receptor types. Its action is potent and of long duration in models for antipsychotic activity (4 h ED50s PO are 0.017 mg/kg for antagonism of apomorphine-induced climbing in mice and 0.028 mg/kg for antagonism of amphetamine-induced locomotion in rats). In contrast to its high potency in models for antipsychotic activity, BRL 34778 is much weaker in models for extrapyramidal effects and sedation (4 h ED50s PO are 2.4 mg/kg for inducing catalepsy in rats and 1.14 mg/kg for inhibition of rearing behaviour in rats). These data indicate potent activity of BRL 34778 in models for antipsychotic activity but low activity in models for extrapyramidal effects and sedation.
Adenylyl Cyclase Inhibitors↗
Human pharmacology of renzapride: a new gastrokinetic benzamide without dopamine antagonist properties.
The activity of the substituted benzamide renzapride on the upper gastrointestinal tract has been investigated. It has been shown to enhance stomach emptying in normal subjects; doses of 2 and 5 mg decreasing by 21 and 37% respectively the volume of gastric contents aspirated 80 min after a test meal. Renzapride was found to reduce the oro-caecal transit time as assessed by the lactulose/breath hydrogen method in a dose related manner from 0.2 to 5 mg; the later dose producing a 62% reduction. Finally renzapride was shown not to elevate plasma prolactin at a dose of 5 mg, a finding consistent with lack of dopamine receptor antagonism.
Adult↗
Effects of propoxyphene, ethoheptazine, and azabicyclane on schedule-controlled responding: attenuation by pentobarbital but not naloxone.
The effects of propoxyphene, ethoheptazine, and azabicyclane, alone and in combination with 1 mg/kg naloxone, were studied in pigeons responding under a multiple fixed ratio, fixed interval schedule of food presentation. Low doses of pentobarbital (3, 5.6, and 10 mg/kg) attenuated the rate-decreasing effects produced by 20 mg/kg propoxyphene, ethoheptazine, and azabicyclane. Naloxone antagonized the rate-decreasing effects produced by 10 mg/kg azabicyclane but did not antagonize the rate-decreasing effects of propoxyphene or ethoheptazine.
Analgesics, Opioid↗
Efficiency, Na+/K+ selectivity and temperature dependence of ion transport through lipid membranes by (221)C10-cryptand, an ionizable mobile carrier.
The kinetics of Na+ and K+ transport across the membrane of large unilamellar vesicles (LUV) were determined at two pH's when transport was induced by (221)C10-cryptand (diaza-1,10-decyl-5-pentaoxa-4,7,13,16,21-bicyclo [8.8.5.] tricosane) at various temperatures, and by nonactin at 25 degrees C and (222)C10-cryptand at 20 and 25 degrees C. The rate of Na+ and K+ transport by (221)C10 saturated with the cation and carrier concentrations. Transport was noncooperative and exhibited selectivity for Na+ with respect to K+. The apparent affinity of (221)C10 for Na+ was higher and less pH-dependent than that for K+, and seven times higher than the affinity for Na+ of nonactin. Its enthalpy was higher than that of (222)C10 for K+ ions (20.5 vs. 1.7 kcal . mole-1). The efficiency of (221)C10 transport of Na+ was pH- and carrier concentration-dependent, and was similar to that of nonactin; its activation energy was similar to that for (222)C10 transport of K+ (35.5 and 29.7 kcal . mole-1, respectively). The reaction orders in cation n(S) and in carrier m(M), respectively, increased and decreased as the temperature rose, and were both independent of carrier or cation concentrations; in most cases, they varied slightly with the pH. n(S) varied with the cation at pH 8.7 and with the carrier for Na+ transport only, while m(M) always depended on the type of cation and carrier. Results are discussed in terms of the structural, physico-chemical and electrical characteristics of carriers and complexes.
Bridged Bicyclo Compounds↗
Transport of alkali cations through thin lipid membranes by (222)C10-cryptand, an ionizable mobile carrier.
The kinetics of K+ and Na+ transport across the membrane of large unilamellar vesicles (L.U.V.) were compared at two pH's, with two carriers: (222)C10-cryptand (diaza-1,10-decyl-5-hexaoxa-4,7,13,16,21,24-bicyclo[8.8.8.]+ ++hexacosane) and valinomcyin, i.e. an ionizable macrobicyclic amino polyether and a neutral macrocyclic antibiotic. The rate of cation transport by (222)C10 saturated as cation and carrier concentrations rose. The apparent affinity of (222)C10 for K+ was higher and less pH dependent than that for Na+ but resembled the affinity of valinomycin for K+. The efficiency of (222)C10 transport of K+ decreased as the pH fell and the carrier concentration rose, and was about ten times lower than that of valinomycin. Noncompetitive K+/Na+ transport selectivity of (222)C10 decreased as pH, and cation and carrier concentrations rose, and was lower than that of valinomycin. Transport of alkali cations by (222)C10 and valinomycin was noncooperative. Reaction orders in cation n(S) and carrier m(M) varied with the type of cation and carrier and were almost independent of pH; n(S) and m(M) were not respectively dependent on carrier or cation concentrations. The apparent estimated constants for cation translocation by (222)C10 were higher in the presence of Na+ than of K+ due to higher carrier saturation by K+, and decreased as pH and carrier concentration increased. Equilibrium potential was independent of the nature of carrier and transported cation. Results are discussed in terms of the structural, physiocochemical and electrical characteristics of carriers and complexes.
Bridged Bicyclo Compounds↗
Solubilization and anionic regulation of cerebral sedative/convulsant receptors labeled with [35S] tert-butylbicyclophosphorothionate (TBPS).
Binding activity for the cage convulsant [35S]-tert- butylbicyclophosphorothionate , which appears to label a site closely associated with the chloride ionophore of the GABAA /benzodiazepine receptor complex has been solubilized from rat cerebral cortex using the zwitterionic detergent CHAPS . Of several detergents screened, only CHAPS and CHAPSO were capable of solubilizing the binding activity with good recovery. The pharmacologic specificity of soluble [35S]-tert- butylbicyclophosphorothionate binding is very similar to the membrane state. In both the membrane and soluble state, [35S]-tert- butylbicyclophosphorothionate binding is enhanced by anions which support inhibitory post-synaptic potentials (" Eccles anions"), suggesting that [35S]-t- butylbicyclophosphorothionate may label chloride channels though to be involved in these potentials. Since this solubilization procedure also preserves GABA and benzodiazepine binding and their regulation by drugs such as barbiturates, purification and isolation of the macromolecular complex including chloride channel and GABA-benzodiazepine sites may be feasible.
Animals↗
Convulsant and anti-convulsant gammabutyrolactones bind at the picrotoxinin/T-butylbicyclophosphorothionate (TBPS) receptor.
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4-Butyrolactone↗
Radiation inactivation of brain [35S]t-butylbicyclophosphorothionate binding sites reveals complicated molecular arrangements of the GABA/benzodiazepine receptor chloride channel complex.
[35S]t-Butylbicyclophosphorothionate ([35S]TBPS), a bicyclic cage convulsant, binds to the anion gating mechanism of the GABA/benzodiazepine receptor chloride channel complex. Using a carefully calibrated radiation inactivation technique, the molecular weight of [35S]TBPS binding complexes from frozen rat cerebral cortex was estimated to be 137,000 daltons. The GABA agonist muscimol reduced [35S]TBPS binding to 0-10% of the control value, in a way which is independent of the radiation dose. This shows that the GABA receptor (Mw = 55,000 daltons) is included in the 137,000-dalton [35S]-TBPS binding complex; the [35S]TBPS binding protein alone accounts for 137,000-55,000 = 82,000 daltons. The pyrazolopyridazine etazolate (SQ 20.009) and etomidate in appropriate concentrations both reduced specific binding of [35S]TBPS. The ability of SQ 20.009 and etomidate to reduce [35S]TBPS binding was greatly reduced by exposure to low radiation doses, suggesting that SQ 20.009 and etomidate reduce [35S]TBPS binding by an allosteric mechanism requiring a molecular structure of 450,000-500,000 daltons. Benzodiazepine agonists (ethyl 4-methoxymethyl-6-benzyloxy-beta-carboline-3-carboxylate, ZK 93423) and inverse agonists (methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate, DMCM) enhance and reduce [35S]TBPS binding, respectively, in repeatedly frozen and washed membrane preparations. The effects of ZK 93423 and DMCM on [35S]TBPS binding disappeared upon exposure of membranes to low radiation doses. This suggests that the benzodiazepine receptor site interacts allosterically with the [35S]TBPS binding site, requiring a molecular complex of at least c. 400,000 daltons. The [35S]TBPS site alone in these latter conditions of membrane preparation (repeatedly frozen/washed) revealed a molecular weight of 221,000 daltons (TBPS-site + GABA receptor + unknown structures). The number of binding sites for [35S]TBPS (145 pmol/g tissue) was only slightly higher than for [3H]flunitrazepam (130 pmol/g tissue) in cerebral cortex. These results are all consonant with the conclusion that the GABA/BZ receptor chloride channel complex is composed of highly integrated multimeric subunits, tentatively accounted for by a tetramic complex of molecular weight 548,000 daltons.
Animals↗