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PubMed1993

Synthesis and CLOGP correlation of imidooxy anticonvulsants.

Continuing structure-activity studies on the anticonvulsant activity of analogs of N-(benzyloxy)-2-azaspiro[4.4]nonane-1,3-dione (2a), which displayed anti-electroshock seizure (MES) activity and a protective index (TD50/ED50) of > 4.5 are reported. An in-depth analysis of this moiety was studied employing the Topliss structure activity and the Craig plot analytical approaches as well as a semiempirical method. CLOG P analysis was also applied to this series after experimentally determining the NOR fragment. All compounds were minimized and these physicochemical parameters correlated to anticonvulsant activity. Several interesting substituted benzyloxy compounds emerged from this study: the 2',4'-dichloro (2b), 4'-(trifluoromethyl) (2c), 2'-bromo (2d), 3'-chloro (2o), 2'-chloro (2r), 2'-fluoro (2p), and 3'-fluoro (2w) analogs, all of which had comparable, or better activity than the parent unsubstituted analog (2a). X-ray crystal analysis of the active 2a versus inactive N-benzyl-2-azaspiro[4.4]nonane-1,3-dione (10) is discussed.

Animals↗

PubMed2002

Anthelmintic paraherquamides are cholinergic antagonists in gastrointestinal nematodes and mammals.

Oxindole alkaloids in the paraherquamide/marcfortine family exhibit broad-spectrum anthelmintic activity that includes drug-resistant strains of nematodes. Paraherquamide (PHQ), 2-deoxoparaherquamide (2DPHQ), and close structural analogs of these compounds rapidly induce flaccid paralysis in parasitic nematodes in vitro, without affecting adenosine triphosphate (ATP) levels. The mechanism of action of this anthelmintic class was investigated using muscle tension and microelectrode recording techniques in isolated body wall segments of Ascaris suum. None of the compounds altered A. suum muscle tension or membrane potential. However, PHQ blocked (when applied before) or reversed (when applied after) depolarizing contractions induced by acetylcholine (ACh) and the nicotinic agonists levamisole and morantel. These effects were mimicked by the nicotinic ganglionic blocker mecamylamine, suggesting that the anthelmintic activity of PHQ and marcfortines is due to blockade of cholinergic neuromuscular transmission. The effects of these compounds were also examined on subtypes of human nicotinic ACh receptors expressed in mammalian cells with a Ca2+ flux assay. 2DPHQ blocked nicotinic stimulation of cells expressing alpha3 ganglionic (IC50 approximately 9 microm) and muscle-type (IC50 approximately 3 microm) nicotinic cholinergic receptors, but was inactive at 100 microm vs. the alpha7 CNS subtype. PHQ anthelmintics are nicotinic cholinergic antagonists in both nematodes and mammals, and this mechanism appears to underlie both their efficacy and toxicity.

Animals↗

PubMed1996

Genotoxic effects of bistratene A on human lymphocytes.

Bistratene A, a toxin isolated from the colonial ascidian Lissoclinum bistratum causes a decrease in mitotic index and retardation of lymphocyte proliferation kinetics when it is added at 48 h to 72-h human lymphocyte cultures. In the same cultures, the incidence of sister chromatid exchanges was not altered by this compound. We also observed an increase in the number of polyploid cells in the cultures, and alterations of the beta-tubulin organization by immunocytochemistry with an antibody against beta-tubulin. Bistratene A induces DNA damage in a dose-dependent fashion in leukocytes, as measured by the alkaline single cell gel electrophoresis assay. These results show that bistratene A interferes with microtubule assembly, is cytotoxic and cytostatic, and that it causes DNA damage.

Acetamides↗

PubMed2002

Characteristic reactions and properties of C-apical O-equatorial (O-cis) spirophosphoranes: effect of the sigma(P)(-)(O) orbital in the equatorial plane and isolation of a hexacoordinate oxaphosphetane as an intermediate of the Wittig type reaction of 10-P-5 phosphoranes.

Novel spirophosphoranes (O-cis) that exhibit reversed apicophilicity having an apical carbon-equatorial oxygen array in a five-membered ring showed enhanced reactivity toward nucleophiles such as n-Bu(4)N(+)F(-) or MeLi in comparison with the corresponding stable isomeric spirophosphoranes (O-trans) having an apical oxygen-equatorial carbon configuration. The enhanced reactivity of the O-cis isomer could be explained by the presence of a lower-lying sigma(P)(-)(O(equatorial)) orbital as the reacting orbital in the equatorial plane, whereas the corresponding orbital is a higher-lying sigma(P)(-)(C(equatorial)) in the O-trans isomer. Density functional theory (DFT) calculation on the actual compounds provided theoretical support for this assumption. In addition, we found that the benzylic anion alpha to the phosphorus atom in O-cis benzyl phosphorane is much more stable than that generated from the corresponding O-trans compounds. The experimental results were considered to be due to the n(C) --> sigma(P)(-)(O) interaction in the O-cis anion, and this was confirmed by DFT calculations. Furthermore, the hexacoordinate anionic species derived from the reaction of the benzylic anion from O-cis benzylphosphorane with an aldehyde was also found to be stabilized as compared with analogous species from the corresponding O-trans isomer. The first X-ray structural characterization of a hexacoordinate phosphate intermediate in the Wittig type reaction using pentacoordinate phosphoranes is reported.

Aldehydes↗

PubMed1987

Tiaspirone in schizophrenia.

It was predicted that tiaspirone, a novel compound, would benefit schizophrenic patients since in animal experiments it is a potent dopamine blocker. Following a placebo washout period of 1 to 2 weeks, 14 patients were treated for 28 days with the drug in a single-blind, dose ranging trial. GAS, NOSIE, and BPRS scores all showed significant improvement. No serious adverse effects were found. The absence of extrapyramidal symptoms was particularly encouraging since 10 of the 14 subjects had previously had them on other neuroleptics. Tiaspirone may represent a step forward in the search for a safer antipsychotic.

Adolescent↗

PubMed2002

Studies of polyphotochromic behaviour of supermolecules by NMR spectroscopy. Part 1. A bis-spirooxazine with a (Z)-ethenic bridge between each moiety.

The photoproducts resulting from the irradiation of a closed colourless biphotochromic molecule formed by two spironaphthoxazine entities linked through an ethenic bridge and its model compound, a singular spironaphthoxazine joined by a double bond to a 2-methoxynaphthalene nucleus in the Z configuration have been studied by high resolution 1H NMR spectroscopy. At low temperature, a clean conversion between closed and open structures has been observed with the demonstration of mono and bi opening of the biphotochromic molecule. In contrast, studies at ambient temperature have implied an irreversible loss of the photochromic properties, with the formation of diastereoisomers, resulting from the cyclisation-oxidation reaction of the systems. But, by carrying out experiments on degassed samples, a significant reversion to closed initial structures was observed.

Cyclization↗

PubMed2001

Structure-based design of novel anticancer agents.

Recently identified agents that interact with cytoskeletal elements such as tubulin include synthetic spiroketal pyrans (SPIKET) and monotetrahydrofuran compounds (COBRA compounds). SPIKET compounds target the spongistatin binding site of beta-tubulin and COBRA compounds target a unique binding cavity on alpha-tubulin. At nanomolar concentrations, the SPIKET compound SPIKET-P causes tubulin depolymerization and exhibits potent cytotoxic activity against cancer cells. COBRA-1 inhibits GTP-induced tubulin polymerization. Treatment of human breast cancer and brain tumor cells with COBRA-1 caused destruction of microtubule organization and apoptosis. Other studies have identified some promising protein tyrosine kinase inhibitors as anti-cancer agents. These include EGFR inhibitors such as the quinazoline derivative WHI-P97 and the leflunomide metabolite analog LFM-A12. Both LFM-A12 and WHI-P97 inhibit the in vitro invasiveness of EGFR positive human breast cancer cells at micromolar concentrations and induce apoptotic cell death. Dimethoxyquinazoline compounds WHI-P131 and WHI-P154 inhibit tyrosine kinase JAK3 in leukemia cells. Of particular interest is WHI-P131, which inhibits JAK3 but not JAK1, JAK2, SYK, BTK, LYN, or IRK at concentrations as high as 350 microM. Studies of BTK inhibitors showed that the leflunomide metabolite analog LFM-A13 inhibited BTK in leukemia and lymphoma cells. Consistent with the anti-apoptotic function of BTK, treatment of leukemic cells with LFM-A13 enhanced their sensitivity to chemotherapy-induced apoptosis.

Animals↗

PubMed1984

Amine fluorescamine compounds inhibit oxidative phosphorylation in rat liver mitochondria.

The reaction of fluorescamine with ammonia, benzylamine, o,p-dimethylbenzylamine, 2-phenylethylamine, p-aminobenzoic acid, and the mycosamine-containing macrolide antibiotic, amphotericin B, yield compounds which induce significant effects on mitochondrial activities. From their effects on energy-yielding processes which lead to transmembranous proton movements, the compounds may be divided into three classes. While all modifiers significantly inhibit proton movement induced by both ATP hydrolysis and electron transfer in mitochondria, their influence on the primary energy yielding steps are quite different. Class I modifiers, e.g., the compound made from amphotericin B, inhibit electron transfer but have no effect on the Pi release associated with ATP hydrolysis. Class II modifiers, e.g., the compound made from benzylamine, inhibit respiration but stimulate Pi release. Class III modifiers, e.g., the compound made from p-aminobenzoic acid, on the other hand, only slightly increase Pi release but have no effect on redox reactions. These and other effects of the modifiers are taken to mean that the proton movements and their associated energy-yielding processes are only linked indirectly. The effects of the modifiers on State 3 mitochondrial activities were also investigated. Although all the modifiers decrease the rates of both State 3 respiration and its coupled ATP synthesis, the efficiency of energy conversion measured by the P/O ratio remains unaltered.

Adenosine Triphosphatases↗

PubMed1996

Diarylspiro[2.4]heptenes as orally active, highly selective cyclooxygenase-2 inhibitors: synthesis and structure-activity relationships.

A novel series of 5,6-diarylspiro[2.4]hept-5-enes was shown to provide highly potent and selective cyclooxygenase-2 (COX-2) inhibitors. A study of structure-activity relationships in this series suggests that 3,4-disubstituted phenyl analogs are generally more selective than 4-substituted phenyl analogs and that replacement of the methyl sulfone group on the 6-phenyl ring with a sulfonamide moiety results in compounds with superior in vivo pharmacological properties, although with lower COX-2 selectivity. Several compounds have been shown to possess promising pharmacological properties in adjuvant-induced arthritis and edema analgesia models. The absence of gastrointestinal (GI) toxicity at 200 mpk of several selected compounds in rats and mice corresponds well with the weak potency for inhibition of COX-1 observed in the enzyme assay. Methyl sulfone 55 and sulfonamide 24 were shown to have superior in vivo pharmacological profiles, low GI toxicity, and good oral bioavailability and duration of action.

Analgesics↗

PubMed2002

Synthesis, cytotoxicity and antiviral activity of N,N'-bis-5-nitropyrimidyl derivatives of dispirotripiperazine.

During the search for new antivirals, various N,N'-bis-5-pyrimidyl derivatives of 3,12-diaza-6,9-diazonia(5,2,5,2)dispirohexadecane dichloride (dispirotripiperazine) were synthesized. To reveal relationships between chemical structure and antiviral activity, the compounds were characterized by fast atom bombardment mass, nuclear magnetic resonance, infra red spectroscopy, and elemental analysis and examined for cytotoxicity, inhibition of cell growth and antiviral activity under in vitro conditions. The results of this study demonstrate an excellent compatibility of the test compounds for confluent as well as proliferating cells and a potent structure-dependent inhibition of herpes simplex virus type 1 replication when added during viral adsorption. Functional group analysis revealed that both the dispirotripiperazine as well as the pyrimidine ring with a nitro group in the 5 position are necessary for activity. A reduction of electron density in the terminal pyrimidine rings enhanced the antiviral activity whereas electron donor substitutions reduced it. Introduction of a methyl group in position 2 of the pyrimidine had no influence on cytotoxicity or antiviral activity.

Animals↗

PubMed2003

A comparison of in vitro acylcarnitine profiling methods for the diagnosis of classical and variant short chain acyl-CoA dehydrogenase deficiency.

BACKGROUND: Homozygosity and compound heterozygosity for the short chain acyl-CoA dehydrogenase (SCAD) gene sequence variants 625G-->A and 511C-->T are associated with ethylmalonic aciduria (EMA), a biochemical indicator of SCAD deficiency. The clinical and biochemical implications of these variants are not fully understood. The effect of these variants on the accumulation of butyrylcarnitine by fibroblasts in culture was studied. METHODS: In vitro acylcarnitine profiling in fibroblasts was carried out using [U-13C]-labeled or unlabeled palmitate in the presence of excess L-carnitine, with or without a medium chain acyl-CoA dehydrogenase (MCAD) inhibitor. Acylcarnitines were analyzed using tandem mass spectrometry. 625G/625G (wild type), 625G/625A and 625A/625A (variant) control fibroblasts were compared with fibroblasts from patients homozygous for inactivating SCAD mutations (SCAD deficient) and from patients with EMA who were homozygous or compound heterozygous for the SCAD variants. RESULTS: Variant control and patient fibroblasts accumulated moderate amounts of butyrylcarnitine compared with wild-type controls and in contrast to the significant amount of butyrylcarnitine accumulated by SCAD deficient fibroblasts, regardless of incubation conditions. CONCLUSIONS: Moderately reduced SCAD activity associated with SCAD variants can be detected using in vitro acylcarnitine profiling methods, which may be used as an indirect measure of SCAD activity.

Acyl-CoA Dehydrogenase↗

PubMed1997

The novel compound TDN-345 induces synthesis/secretion of nerve growth factor in C6-10A glioma cells.

A novel compound, TDN-345, not bearing catechol moiety, induced NGF synthesis/secretion in C6-10A glioma cells. Both intracellular and extracellular nerve growth factor (NGF) protein levels increased within 3 h and reached a maximum around 12 h after the addition of TDN-345. The induction of NGF synthesis/secretion by TDN-345 occurred in a concentration-dependent manner, beginning with about 0.1 microM and reaching a maximum at 10 microM. The ED50 was 0.88 microM. The induction was accompanied by an increase in NGF mRNA but not beta-actin mRNA. In a time-course study, the NGF mRNA level was found to reach a maximum 2-3 h after the addition of TDN-345 and then to return to control levels. The induction occurred dose-dependently. The catecholaminergic compound epinephrine, which induces NGF synthesis/secretion, increased the intracellular cyclic AMP content by more than 1000-times at 10 microM. In contrast, TDN-345 did not cause such a prominent increase in cAMP even at 100 microM. These results indicate that TDN-345 induces NGF synthesis/secretion by increasing NGF mRNA expression, and the action of TDN-345 clearly differs from that of epinephrine, as it does not seem to involve cAMP as a second messenger. The results of the present study suggest the existence of a signal transduction pathway for NGF synthesis/secretion which is not mediated by cAMP.

Animals↗

PubMed2000

Effect of SR121463, a selective non-peptide vasopressin V2 receptor antagonist, in a rabbit model of ocular hypertension.

The activity on intraocular pressure (IOP) of SR121463, a selective non-peptide arginin-vasopressin (AVP) V2 receptor antagonist, was investigated in a rabbit model of ocular hypertension. We first demonstrated that, in vitro, SR121463 displayed high competitive affinity for rabbit vasopressin V2 receptors (Ki = 2.1 +/- 1.2 nM). In vivo, SR121463 was instilled once (at concentrations ranging from 0.1 to 3%), or for 10 days (20 instillations) at 1% concentration, in the eye of ocular hypertensive rabbits (intraocular injection of 0.14 mg alpha-chymotrypsin). SR121463 also was instilled at 1% in the normotensive eye or intravenously injected (100 microg/kg) to ocular hypertensive rabbits. SR121463 was compared to timolol 0.5% or to clonidine 0.25%. Additionally, local and systemic safety aspects were examined. Results showed that SR121463 was locally well-tolerated and had no anesthetic effect. A significant decrease in IOP of the hypertensive eye was observed for concentrations of SR121463 > or =1%. This decrease was comparable to that obtained with reference compounds. A similar activity was found after intravenous administration. No tachyphylaxis was observed after 10 days, and no contralateral or systemic effect was noted. Also, when applied on the normotensive eye or when intravenously injected, SR121463 had no effect on the normotensive eye. These results on IOP and the good local and systemic safety profile, suggest that a potent vasopressin V2 receptor antagonist, SR121463, could be of value for the treatment of glaucoma, through a mechanism of action that remains to be elucidated.

Administration, Oral↗

PubMed2004

Total synthesis of (+/-)-halichlorine, (+/-)-pinnaic acid, and (+/-)-tauropinnaic acid.

The related marine natural products halichlorine, pinnaic acid, and tauropinnaic acid have been synthesized. The described route provided access to all three compounds from a common, late-stage intermediate. The synthesis began with 1-pyrrolidino-1-cyclopentene from which an intermediate possessing the three contiguous stereocenters of the natural products was synthesized in just four steps. Olefin cross metathesis followed by a hydrogenation/hydrogenolysis reaction stereoselectively formed the piperidine ring. Use of a beta-lactam group provided internal protection for the highly congested nitrogen atom during side-chain elaboration. The beta-lactam was subsequently reduced directly to an amino aldehyde, which after the Horner-Wadsworth-Emmons reaction was elaborated to pinnaic acid. The same amino aldehyde was also transformed into halichlorine after a thiol-mediated cyclization sequence to form the dehydroquinolizidine ring system.

Alkaloids↗

PubMed1992

Central cholinergic agents. III. Synthesis of 2-alkoxy-2,8- diazaspiro[4.5]decane-1,3-diones as muscarinic agonists.

A series of 2-alkoxy-2,8-diazaspiro[4.5]decane-1,3-diones and related compounds were synthesized and tested for muscarinic receptor binding affinity using [3H]pirenzepine and [3H]oxotremorine M as ligands. They were also evaluated for agonistic activities in the guinea pig ileum assay. 2-Methoxy- 2,8-diazaspiro[4.5]decane-1,3-dione (1i) was found to be a relatively M1 selective agonist. It reversed CO2-induced impairment of passive avoidance response with long duration of action, but also displayed peripheral effects at low doses. To minimize these side effects, we proposed the idea of conjugation of 1i with a muscarinic antagonist. The carbamate linked conjugate (1u) of 1i with methylatropine was therefore examined.

Animals↗

PubMed2004

In vitro characterization of AR-A000002, a novel 5-hydroxytryptamine(1B) autoreceptor antagonist.

The in vitro pharmacological properties of AR-A000002 ((R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzamide), a novel 5-hydroxytryptamine (5-HT)(1B) receptor antagonist, were studied. AR-A000002 bound with high affinity to guinea pig cortex and recombinant guinea pig 5-HT(1B) receptors (Ki=0.24 and 0.47 nM) and with 10-fold lower affinity to 5-HT(1D) receptors. The compound displayed weak or no affinity for 63 other binding sites tested. In [35S]GTPgammaS assays AR-A000002 showed 50% efficacy and inhibited 5-HT stimulation with 66% and a pA2 value of 8.9. In slices of guinea pig cortex, AR-A000002 enhanced the outflow of [3H]5-HT upon electrical stimulation. The compound blocked sumatriptan-evoked contraction of rabbit saphenous veins without inducing any contraction itself. Thus, in these two systems AR-A000002 behaved as a 5-HT(1B) receptor antagonist. It is concluded that AR-A000002 is a selective high affinity 5HT(1B) receptor ligand that shows partial agonist activity in recombinant systems. In native tissues AR-A000002 behaves as a 5-HT(1B) receptor antagonist.

Animals↗

PubMed1980

Differential effects on energy transduction processes by fluorescamine derivatives in rat liver mitochondria.

Intact rat liver mitochondria were treated with compounds derived from the reaction of fluorescamine with various types of primary amines, including the mycosamine-containing antibiotics amphotericin B and nystatin. The effect of varying amounts of these compounds on ATPase-linked inorganic phosphate (Pi) formation on oxygen consumption, and on MgATP-linked and succinate-linked proton movements was examined. The antibiotic-fluorescamine compounds did not affect the Pi formation rate but strongly inhibited both the ATPase-linked and the succinate-linked H+ extrusion rates to approximately the same extent. The antibiotic derivatives decreased the oxygen consumption rate, but this effect was much smaller than the decrease in the respiration-dependent proton extrusion rate. The benzylamine-fluorescamine compound significantly increased the Pi formation rate, in contrast to the antibiotic analogues. The benzylamine derivative, like the antibiotic derivatives, inhibited both types of proton extrusion rates. The slight decrease in the oxygen consumption rate caused by the benzylamine derivative was significantly smaller than the corresponding decrease observed with the antibiotic derivatives. These studies, in which fluorescamine derivatives bind reversibly to mitochondria, are compared with previous studies in which fluorescamine itself binds irreversibly to mitochondria and results in a Pi formation rate increase and MgATP- and succinate-linked proton extrusion rate inhibition but has no effect on the oxygen consumption rate.

Adenosine Triphosphatases↗

PubMed1999

Humanization of mouse 5-hydroxytryptamine1B receptor gene by homologous recombination: in vitro and in vivo characterization.

We replaced the coding region of the murine 5-hydroxytryptamine (5-HT)1B receptor by the human 5-HT1B receptor using homologous recombination in embryonic stem cells and generated and characterized homozygous transgenic mice that express only the human (h) 5-HT1B receptor. The distribution patterns of h5-HT1B and murine (m) 5-HT1B receptor mRNA and binding sites in brain sections of transgenic and wild-type mice were identical as measured by in situ hybridization histochemistry and radioligand receptor autoradiography. When measured in parallel under identical conditions, the h5-HT1B receptor expressed in mouse brain had the same pharmacological characteristics as that in human brain. Stimulation by 5-HT1B agonists of [35S]guanosine-5'-O-(3-thio)triphosphate binding in brain sections demonstrated the functional coupling of the h5-HT1B receptor to G proteins in mouse brain. In tissue slices from various brain regions, electrically stimulated [3H]5-HT release was not modified by 5-HT1B agonists in tissue from either transgenic and wild-type mice; a 5-HT1B antagonist enhanced electrically stimulated [3H]5-HT release in wild-type mouse brain, but was ineffective in the transgenics. The centrally active 5-HT1A/5-HT1B agonist RU24969 induced hypothermia but did not increase locomotor activity in the transgenic mice. The ineffectiveness of RU24969 in the transgenic mice could be due to the lower affinity of the compound for the h5-HT1B receptor compared with the m5-HT1B receptor. The present study demonstrates a complete replacement of the mouse receptor by its human receptor homolog and a functional coupling to G proteins. However, modulation of [3H]5-HT release could not be shown. Furthermore, behavioral effects were not clearly observed, which may be due to a lack of appropriate tools.

Animals↗