1-(2,5-Dichlorophenyl)-3-methyl-5-phenyl-1H-pyrazole.
Explore the source record for details and available documents.
Antitubercular Agents↗
Biomedical subjects
Peter A Crooks
Publications and source records attributed to Peter A Crooks.
(E)-N-[(Benzo[b]thiophen-3-yl)methylene]-N'-(2,5-dichlorophenyl)hydrazine.
Explore the source record for details and available documents.
Antitubercular Agents↗
A duplex "Gemini" prodrug of naltrexone for transdermal delivery.
Transdermal naltrexone delivery is desirable in the treatment of narcotic dependence and alcoholism. The purpose of this study was to increase the delivery rate of naltrexone (NTX) across human skin by using a novel prodrug. A duplex "gemini" prodrug of naltrexone was synthesized and evaluated. In vitro human skin permeation rates of naltrexone and prodrug were measured using a flow-through diffusion cell system. Drug concentrations in the skin were quantitated at the end of the diffusion experiment. The prodrug was hydrolyzed on passing through the skin and appeared mainly as naltrexone in the receiver compartment. The prodrug provided a significantly higher naltrexone equivalent flux across human skin in vitro than naltrexone base. The naltrexone equivalent solubilities of naltrexone and the prodrug in the donor solution were not significantly different. No significant increase in drug concentration in the skin after prodrug treatment, as compared to naltrexone, was observed. The naltrexone equivalent permeability from the prodrug exceeded the permeability of naltrexone base by two-fold. Due to the design of this prodrug, toxicities associated with this compound should be nonexistent, because only naltrexone and carbon dioxide (carbonic acid) are released when the prodrug is cleaved.
Administration, Cutaneous↗
Lobeline analogs with enhanced affinity and selectivity for plasmalemma and vesicular monoamine transporters.
Lobeline attenuates the behavioral effects of psychostimulants in rodents and inhibits the function of nicotinic receptors (nAChRs), dopamine transporters (DATs), and vesicular monoamine transporters (VMAT2s). Monoamine transporters are considered valid targets for drug development for the treatment of methamphetamine abuse. In the current study, a series of lobeline analogs were evaluated for affinity and selectivity at these targets. None of the analogs was more potent than nicotine at the [3H]methyllycaconitine binding site (alpha7* nAChR subtype). Lobeline tosylate was equipotent with lobeline in inhibiting [3H]nicotine binding but 70-fold more potent in inhibiting nicotine-evoked 86Rb+ efflux, demonstrating antagonism of alpha4beta2* nAChRs. Compared with lobeline, the defunctionalized analogs lobelane, mesotransdiene, and (-)-trans-transdiene showed dramatically reduced affinity at alpha4beta2* nAChRs and a 15- to 100-fold higher affinity (Ki = 1.95, 0.58, and 0.26 microM, respectively) at DATs. Mesotransdiene and (-)-trans-transdiene competitively inhibited DAT function, whereas lobelane and lobeline acted noncompetitively. 10S/10R-MEPP [N-methyl-2R-(2R/2S-hydroxy-2-phenylethyl)6S-(2-phenylethyl)piperidine] and 10R-MESP [N-methyl-2R-(2R-hydroxy-2-phenylethyl)6S-(2-phenylethen-1-yl)piperidine] were 2 to 3 orders of magnitude more potent (Ki = 0.01 and 0.04 microM, respectively) than lobeline in inhibiting [3H]serotonin uptake; 10S/10R-MEPP showed a 600-fold selectivity for this transporter. Uptake results using hDATs and human serotonin transporters expressed in human embryonic kidney-293 cells were consistent with native transporter assays. Lobelane and ketoalkene were 5-fold more potent (Ki = 0.92 and 1.35 microM, respectively) than lobeline (Ki = 5.46 microM) in inhibiting [3H]methoxytetrabenazine binding to VMAT2 in vesicle preparations. Thus, structural modification (defunctionalization) of the lobeline molecule markedly decreases affinity for alpha4beta2* and alpha7* nAChRs while increasing affinity for neurotransmitter transporters, affording analogs with enhanced selectivity for these transporters and providing new leads for the treatment of psychostimulant abuse.
Aconitine↗
Subtype-selective nicotinic receptor antagonists: potential as tobacco use cessation agents.
N-n-Alkylpicolinium and N,N'-alkyl-bis-picolinium analogues were assessed in nicotinic receptor (nAChR) assays. The most potent and subtype-selective analogue, N,N'-dodecyl-bis-picolinium bromide (bPiDDB), inhibited nAChRs mediating nicotine-evoked [(3)H]dopamine release (IC(50)=5 nM; I(max) of 60%), and did not interact with alpha4beta2* or alpha7* nAChRs. bPiDDB represents the current lead compound for development as a tobacco use cessation agent.
Animals↗
Development of subtype-selective ligands as antagonists at nicotinic receptors mediating nicotine-evoked dopamine release.
N-n-Alkylation of nicotine converts it from an agonist into an antagonist at neuronal nicotinic acetylcholine receptor subtypes mediating nicotine-evoked dopamine release. Conformationally restricted analogues exhibit both high affinity and selectivity at this site, and are able to access the brain due to their ability to act as substrates for the blood-brain barrier choline transporter.
Aconitine↗
(Z)-3-(1-Methyl-1H-indol-3-yl)-2-(thiophen-3-yl)acrylonitrile.
The title compound, C16H12N2S, has been synthesized by base-catalyzed condensation of 1-methylindole-3-carboxaldehyde with thiophene-3-acetonitrile. The product assumes an approximately planar Z configuration. The molecule has a thienyl-ring flip disorder.
Acrylonitrile↗
Elimination of alkaloids from plant-derived human monoclonal antibody.
A human antiviral monoclonal antibody (mAb) expressed in transgenic tobacco plants was purified from the tobacco leaf by two different methods. In one method, total protein precipitated with ammonium sulfate was applied to a Hi-Trap protein A column (column method). In the second method, leaf supernatant obtained after liquid nitrogen leaf grinding was directly immunoprecipitated using protein A-agarose beads (immunoprecipitation method). The column and immunoprecipitation methods yielded 0.52 and 0.45 microg of plant-derived mAb (mAb(P))/g, respectively, from fresh leaf tissue. The product derived using the column method exhibited higher binding activity compared to immunoprecipitation-derived product against rabies virus strain CVS-11 in ELISA. Gas chromatography/mass spectrometry analysis, which has a detection limit of 5 pg revealed no detectable levels of nicotine or other related plant alkaloids in the purified mAb(P) from either purification procedure. Thus, both purification methodologies yield mAb(P) uncontaminated with nicotine from the tobacco leaves.
Antibodies, Monoclonal↗
Physicochemical evaluation, in vitro human skin diffusion, and concurrent biotransformation of 3-O-alkyl carbonate prodrugs of naltrexone.
PURPOSE: The purpose of this study was to evaluate the physicochemical properties and in vitro human skin diffusion of the 3-O-alkyl carbonate prodrugs of naltrexone (NTX). METHODS: Melting points and heats of fusion (deltaHf) were determined using differential scanning calorimetry. In vitro human skin permeation rates of NTX and its prodrugs were measured using a flowthrough diffusion cell system. Drug disposition in the skin was quantified at the end of the diffusion experiment. The solubilities of the drugs were determined in mineral oil and isotonic buffer. Partitioning of the prodrugs from vehicle to skin was determined using isolated sheets of human stratum corneum (SC). RESULTS: All the prodrugs hydrolyzed to NTX on passing through the skin, and the methyl NTX-3-O-carbonate (ME-NTX) provided the highest NTX flux, apparent permeability coefficient (Kp), and calculated relative thermodynamic activity from the melting point and deltaHf. The ME-NTX SC/vehicle partition coefficient was the highest of the prodrug series, although similar to the NTX SC/vehicle partition coefficient value. The shortest chain prodrugs underwent the highest extent of bioconversion to NTX upon passing through the skin. CONCLUSIONS: Within this 3-O-alkyl carbonate prodrug series, the shortest chain prodrug was the most skin-permeable compound with the highest partition coefficient and a significant extent of bioconversion.
Biotransformation↗
Molecular pathway for thymoquinone-induced cell-cycle arrest and apoptosis in neoplastic keratinocytes.
Thymoquinone (TQ), the most abundant constituent in black seed, was shown to possess potent chemopreventive activities against DMBA-initiated TPA-promoted skin tumors in mice. Despite the potential interest in TQ as a skin antineoplastic agent, its mechanism of action has not been examined yet. Using primary mouse keratinocytes, papilloma (SP-1) and spindle (I7) carcinoma cells, we studied the cellular and molecular events involved in TQ's antineoplastic activity. We show that non-cytotoxic concentrations of TQ reduce the proliferation of neoplastic keratinocytes by 50%. The sensitivity of cells to TQ treatment appears to be stage dependent such that papilloma cells are twice as sensitive to the growth inhibitory effects of TQ as the spindle cancer cells. TQ treatment of SP-1 cells induced G0/G1 cell-cycle arrest, which correlated with sharp increases in the expression of the cyclin-dependent kinase inhibitor p16 and a decrease in cyclin D1 protein expression. TQ-induced growth inhibition in I7 cells by inducing G2/M cell-cycle arrest, which was associated with an increase in the expression of the tumor suppressor protein p53 and a decrease in cyclin B1 protein. At longer times of incubation, TQ induced apoptosis in both cell lines by remarkably increasing the ratio of Bax/Bcl-2 protein expression and decreasing Bcl-xL protein. The apoptotic effects of TQ were more pronounced in SP-1 than in I7 cells. Collectively, these findings support a potential role for TQ as a chemopreventive agent, particularly at the early stages of skin tumorigenesis.
Animals↗
Spectrophotometric and steady-state kinetic analysis of the biosynthetic arginine decarboxylase of Yersinia pestis utilizing arginine analogues as inhibitors and alternative substrates.
The PLP-dependent, biosynthetic arginine decarboxylase (ADC) of Yersinia pestis was investigated using steady-state kinetics employing structural analogues of arginine as both alternative substrates and competitive inhibitors. The inhibitor analysis indicates that binding of the carboxyl and guanidinium groups of the substrate, l-arginine, provides essentially all of the free energy change realized upon substrate binding in the ground state. Furthermore, recognition of the guanidinium group is primarily responsible for substrate specificity. Comparison of the steady-state parameters for a series of alternative substrates that contained chemically modified guanidinium moieties provides evidence of a role for induced fit in ADC catalysis. ADC was also characterized by UV/vis and fluorescence spectrophotometry in the presence or absence of a number of arginine analogues. The enzyme complexes formed served as models for the adsorption complex and the external aldimine complex of the enzyme with the substrate.
Amino Acid Sequence↗
(Z)-2-(1H-Indol-3-ylmethylene)-1-azabicyclo[2.2.2]octan-3-one.
The title compound, C(16)H(16)N(2)O, which contains a double bond connecting an azabicyclic ring system to an indol-3-ylmethylene group, crystallizes from a solution in ethyl acetate. The geometries of the two crystallographically independent molecules are nearly identical. The crystal packing of the title compound involves two types of intermolecular hydrogen bond.
Aza Compounds↗
Two isomers of 2,4-dibenzyl-8-azabicyclo[3.2.1]octan-3-ol.
The crystal structures of the title compounds, 2 alpha,4 alpha-dibenzyl-3 alpha-tropanol (2 alpha,4 alpha-dibenzyl-8-methyl-8-azabicyclo[3.2.1]octan-3 alpha-ol), C(22)H(27)NO, (I), and 2 alpha,4 alpha-dibenzyl-3 beta-tropanol (2 alpha,4 alpha-dibenzyl-8-methyl-8-azabicyclo[3.2.1]octan-3 beta-ol), C(22)H(27)NO, (II), show that both compounds have a piperidine ring in a chair conformation and a pyrrolidine ring in an envelope conformation. Isomer (I) is asymmetric, the benzyl groups having different orientations, whereas isomer (II) is mirror symmetric, and the N and O atoms, the C atom attached to the hydroxy group, and the methyl C atom attached to the N atom lie on the mirror plane. In the crystal structures of both (I) and (II), the molecules are linked together by intermolecular O-H...N hydrogen bonds to form chains that run parallel to the a direction in (I) and parallel to b in (II).
Aza Compounds↗
(Z)-2-(3-hydroxy-4-methoxybenzylidene)-1-azabicyclo[2.2.2]octan-3-one.
Crystals of the title compound, C(15)H(17)NO(3), were obtained from a condensation reaction of 3-hydroxy-4-methoxybenzaldehyde with 1-azabicyclo[2.2.2]octan-3-one and subsequent crystallization of the product from methanol. The title compound, containing a double bond that connects the azabicyclic ring system to the 3-hydroxy-4-methoxybenzylidene group, was obtained with Z geometry.
Crystallography, X-Ray↗
NADPH oxidase activity is essential for Keap1/Nrf2-mediated induction of GCLC in response to 2-indol-3-yl-methylenequinuclidin-3-ols.
Glutamate cysteine ligase, the rate-limiting enzyme for the synthesis of glutathione, represents an important component of chemoprevention paradigms. GCLC and GCLM, the genes encoding glutamate cysteine ligase subunits, are induced by indoles, such as indomethacin. Novel functionalized indole analogues and other structurally related compounds were synthesized and used for a comparative structure analysis of GCLC induction. Use of mouse embryo fibroblasts null for Nrf2 (nuclear factor-erythroid 2p45-related transcription factor) and HepG2 cells overexpressing Keap1 demonstrated that indole analogue-mediated GCLC expression was regulated by Nrf2-Keap1 interactions. Indole analogues capable of inducing GCLC were found to increase NADPH oxidase activity. Indole analogues unable to induce GCLC did not increase oxidase activity. HepG2 cells transfected with FLAG/Keap1 were exposed to indomethacin, and the redox state of Keap1 cysteine residues was assessed. The data indicated that Keap1 exhibited several oxidation states that were sensitive to indomethacin treatment. These indomethacin-mediated changes in thiol oxidation states were suppressed by diphenyleneiodonium, a NADPH oxidase inhibitor. Diphenyleneiodonium also suppressed indole analogue-mediated increases in GCLC mRNA. In summary, the use of the indole analogues identified NADPH oxidase activity as a novel upstream activity regulating Nrf2/Keap1 signaling of GCLC, provided data supporting the hypothesis that Keap1 is a downstream effector for oxidase activity, and afforded in vivo data to support the hypothesis that Keap1 thiols can act as molecular sensors of reactive oxygen species. Finally, the comparative structure analysis suggests that 2-indol-3-yl-methylenequinuclidin-3-ols may represent a prototype for the development of novel chemopreventative agents able to activate Keap1/Nrf2 signaling.
Animals↗
N-n-alkylpyridinium analogs, a novel class of nicotinic receptor antagonists: selective inhibition of nicotine-evoked [3H] dopamine overflow from superfused rat striatal slices.
Structural simplification of N-n-alkylnicotinium analogs, antagonists at neuronal nicotinic acetylcholine receptors (nAChRs), was achieved by removal of the N-methylpyrrolidino moiety affording N-n-alkylpyridinium analogs with carbon chain lengths of C1 to C20. N-n-Alkylpyridinium analog inhibition of [3H]nicotine and [3H]methyllycaconitine binding to rat brain membranes assessed interaction with alpha4beta2* and alpha7* nAChRs, respectively, whereas inhibition of nicotine-evoked 3H overflow from [3H]dopamine ([3H]DA)-preloaded rat striatal slices assessed antagonist action at nAChR subtypes mediating nicotine-evoked DA release. No inhibition of [3H]methyllycaconitine binding was observed, although N-n-alkylpyridinium analogs had low affinity for [3H]nicotine binding sites, i.e., 1 to 3 orders of magnitude lower than that of the respective N-n-alkylnicotinium analogs. These results indicate that the N-methylpyrrolidino moiety in the N-n-alkylnicotinium analogs is a structural requirement for potent inhibition of alpha4beta2* nAChRs. Importantly, N-n-alkylpyridinium analogs with n-alkyl chains < C10 did not inhibit nicotine-evoked [3H]DA overflow, whereas analogs with n-alkyl chains ranging from C10 to C20 potently and completely inhibited nicotine-evoked [3H]DA overflow (IC50 = 0.12-0.49 microM), with the exceptions of N-n-pentadecylpyridinium bromide (C15) and N-n-eicosylpyridinium bromide (C20), which exhibited maximal inhibition of approximately 50%. The mechanism of inhibition of a representative analog of this structural series, N-n-dodecylpyridinium iodide, was determined by Schild analysis. Linear Schild regression with slope not different from unity indicated competitive antagonism at nAChRs mediating nicotine-evoked [3H]DA overflow and a KB value of 0.17 microM. Thus, the simplified N-n-alkylpyridinium analogs are potent, selective, and competitive antagonists of nAChRs mediating nicotine-evoked [3H]DA overflow, indicating that the N-methylpyrrolidino moiety is not a structural requirement for interaction with nAChR subtypes mediating nicotine-evoked DA release.
Aconitine↗
N,N-disubstituted piperazines: synthesis and affinities at alpha4beta2(*) and alpha7(*) neuronal nicotinic acetylcholine receptors.
A series of N,N-disubstituted piperazines were prepared and evaluated for binding to alpha4beta2(*) and alpha7(*) neuronal nicotinic acetylcholine receptors using rat striatum and whole brain membrane preparations, respectively. This series of compounds exhibited selectivity for alpha4beta2(*) nAChRs and did not interact with the alpha7(*) nAChRs subtype. The most potent analogues were compounds 8b and 8f (K(i)=32 microM). Thus, linking together a pyridine pi-system and a cyclic amine moiety via a piperazine ring affords compounds with low affinity, but good selectivity for alpha4beta2(*) nicotinic receptors.
Animals↗
An in vivo evaluation of the antiseizure activity and acute neurotoxicity of agmatine.
Agmatine, an endogenous cationic amine, exerts a wide range of biological effects, including modulation of glutamate-activated N-methyl-D-aspartate (NMDA) receptor function in the central nervous system (CNS). Since glutamate and the NMDA receptor have been implicated in the initiation and spread of seizure activity, the capacity of agmatine to inhibit seizure spread was evaluated in vivo. Orally administered agmatine (30 mg/kg) protected against maximal electroshock seizure (MES)-induced seizure spread in rats as rapidly as 15 min and for as long as 6 h after administration. Inhibition of MES-induced seizure spread was also observed when agmatine was administered intraperitoneally. Agmatine's antiseizure activity did not appear to be dose-dependent. An in vivo neurotoxicity screen indicated that agmatine was devoid of any acute neurological toxicity at the doses tested. These preliminary data suggest that agmatine has promising anticonvulsant activity.
Agmatine↗