- Dual Sigma-1 receptor antagonists and hydrogen sulfide-releasing compounds for pain treatment: Design, synthesis, and pharmacological evaluation
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The development of σ1 receptor antagonists hybridized with a H2S-donor is here reported. We aimed to obtain improved analgesic effects when compared to σ1 receptor antagonists or H2S-donors alone. In an in vivo
- Dichiara, Maria,Artacho-Cordón, Antonia,Turnaturi, Rita,Santos-Caballero, Miriam,González-Cano, Rafael,Pasquinucci, Lorella,Barbaraci, Carla,Rodríguez-Gómez, Isabel,Gómez-Guzmán, Manuel,Marrazzo, Agostino,Cobos, Enrique J.,Amata, Emanuele
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- Structure-Kinetic Profiling of Haloperidol Analogues at the Human Dopamine D2 Receptor
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Haloperidol is a typical antipsychotic drug (APD) associated with an increased risk of extrapyramidal side effects (EPSs) and hyperprolactinemia relative to atypical APDs such as clozapine. Both drugs are dopamine D2 receptor (D2R) antagonists, with contrasting kinetic profiles. Haloperidol displays fast association/slow dissociation at the D2R, whereas clozapine exhibits relatively slow association/fast dissociation. Recently, we have provided evidence that slow dissociation from the D2R predicts hyperprolactinemia, whereas fast association predicts EPS. Unfortunately, clozapine can cause severe side effects independent of its D2R action. Our results suggest an optimal kinetic profile for D2R antagonist APDs that avoids EPS. To begin exploring this hypothesis, we conducted a structure-kinetic relationship study of haloperidol and revealed that subtle structural modifications dramatically change binding kinetic rate constants, affording compounds with a clozapine-like kinetic profile. Thus, optimization of these kinetic parameters may allow development of novel APDs based on the haloperidol scaffold with improved side-effect profiles.
- Fyfe, Tim J.,Kellam, Barrie,Sykes, David A.,Capuano, Ben,Scammells, Peter J.,Lane, J. Robert,Charlton, Steven J.,Mistry, Shailesh N.
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p. 9488 - 9520
(2019/11/11)
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- Antiangiogenic Effect of (±)-Haloperidol Metabolite II Valproate Ester [(±)-MRJF22] in Human Microvascular Retinal Endothelial Cells
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(±)-MRJF22 [(±)-2], a novel prodrug of haloperidol metabolite II (sigma-1 receptor antagonist/sigma-2 receptor agonist ligand) obtained by conjugation to valproic acid (histone deacetylase inhibitor) via an ester bond, exhibits antiangiogenic activity, being able to reduce human retinal endothelial cell (HREC) viability in a comparable manner to bevacizumab. Moreover, (±)-2 was able to significantly reduce viable cells count, endothelial cell migration, and tube formation in vascular endothelial growth factor A (VEGF-A) stimulated HREC cultures.
- Olivieri, Melania,Amata, Emanuele,Vinciguerra, Shila,Fiorito, Jole,Giurdanella, Giovanni,Drago, Filippo,Caporarello, Nunzia,Prezzavento, Orazio,Arena, Emanuela,Salerno, Loredana,Rescifina, Antonio,Lupo, Gabriella,Anfuso, Carmelina Daniela,Marrazzo, Agostino
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p. 9960 - 9966
(2016/11/19)
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- Involvement of microsomal NADPH-cytochrome P450 reductase in metabolic reduction of drug ketones
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Recently, it was found that the carbonyl group of 1-[3-(4-phenoxyphenoxy)-2-oxopropyl]indole-5-carboxylic acid (5), an inhibitor of the pro-inflammatory enzyme cytosolic phospholipase A2α, is easily reduced by rat liver S9 fractions in vitro. Determination of the inhibitory potency of certain putative inhibitors of carbonyl reducing enzymes on the transformation of the ketone derivative 5 to its alcohol 6 by recombinant microsomal NADPH-cytochrome P450 reductase and by recombinant cytosolic carbonyl reductase-1 now reveals that these compounds show a lack of specificity for these two enzymes in part. Thus, an assignment of the roles of different carbonyl reductases in metabolic keto reduction by the use of inhibitors is problematic. In addition, the ability of NADPH-cytochrome P450 reductase and carbonyl reductase-1 to reduce the ketone groups of the drugs haloperidol and daunorubicin was examined. Under the conditions applied, a pronounced reductive metabolism was only observed for daunorubicin in the presence of microsomal NADPH-cytochrome P450 reductase. Similarly, in rat liver S9 fractions a marked reduction of daunorubicin was seen, while haloperidol was only slightly metabolized to its alcohol. After separation of the S9 homogenate into a microsomal and a cytosolic fraction, it became evident that the ketone groups of daunorubicin, haloperidol and compound 5 were mainly reduced by cytosolic enzymes. However, since microsomes also catalysed these carbonyl reductions to some extent, it can be concluded that microsomal NADPH-cytochrome P450 reductase can contribute to metabolic keto reductions in xenobiotics.
- Lehr, Matthias,Fabian, J?rg,Hanekamp, Walburga
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p. 398 - 404
(2015/09/15)
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- Rabbit 3-hydroxyhexobarbital dehydrogenase is a NADPH-preferring reductase with broad substrate specificity for ketosteroids, prostaglandin D2, and other endogenous and xenobiotic carbonyl compounds
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3-Hydroxyhexobarbital dehydrogenase (3HBD) catalyzes NAD(P) +-linked oxidation of 3-hydroxyhexobarbital into 3-oxohexobarbital. The enzyme has been thought to act as a dehydrogenase for xenobiotic alcohols and some hydroxysteroids, but its physiological function remains unknown. We have purified rabbit 3HBD, isolated its cDNA, and examined its specificity for coenzymes and substrates, reaction directionality and tissue distribution. 3HBD is a member (AKR1C29) of the aldo-keto reductase (AKR) superfamily, and exhibited high preference for NADP(H) over NAD(H) at a physiological pH of 7.4. In the NADPH-linked reduction, 3HBD showed broad substrate specificity for a variety of quinones, ketones and aldehydes, including 3-, 17- and 20-ketosteroids and prostaglandin D2, which were converted to 3α-, 17β- and 20α-hydroxysteroids and 9α,11β- prostaglandin F2, respectively. Especially, α-diketones (such as isatin and diacetyl) and lipid peroxidation-derived aldehydes (such as 4-oxo- and 4-hydroxy-2-nonenals) were excellent substrates showing low Km values (0.1-5.9 μM). In 3HBD-overexpressed cells, 3-oxohexobarbital and 5β-androstan-3α-ol-17-one were metabolized into 3-hydroxyhexobarbital and 5β-androstane-3α,17β-diol, respectively, but the reverse reactions did not proceed. The overexpression of the enzyme in the cells decreased the cytotoxicity of 4-oxo-2-nonenal. The mRNA for 3HBD was ubiquitously expressed in rabbit tissues. The results suggest that 3HBD is an NADPH-preferring reductase, and plays roles in the metabolisms of steroids, prostaglandin D2, carbohydrates and xenobiotics, as well as a defense system, protecting against reactive carbonyl compounds.
- Endo, Satoshi,Matsunaga, Toshiyuki,Matsumoto, Atsuko,Arai, Yuki,Ohno, Satoshi,El-Kabbani, Ossama,Tajima, Kazuo,Bunai, Yasuo,Yamano, Shigeru,Hara, Akira,Kitade, Yukio
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p. 1366 - 1375
(2013/11/19)
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- Electrochemical mechanism and kinetics studies of haloperidol and its assay in commercial formulations
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The kinetics and mechanism for electrochemical reduction of haloperidol, a psychotherapeutic drug used in the treatment of schizophrenia, were studied using square wave and cyclic voltammetries allied to a hanging mercury drop electrode. The experimental and voltammetric parameters were optimized at 0.04 mol L-1 Brinton-Robinson buffer (pH 10), with a pulse potential frequency of 100 s-1, a pulse amplitude of 30 mV and scan increment of 2 mV. Two well-defined peaks were observed, which exhibited properties of fast electron transfer with a strong adsorption process of reactants and products on the electrode surface. The first peak was related to a fast and reversible anion-radical formation originating from the reduction of the carbonyl group, and the second was related to the irreversible reduction of the anion-radical previously formed. Analytical parameters such as: linearity range, equation of the analytical curves, correlation coefficients, detection and quantification limits, recovery efficiency, and relative standard deviation for intraday and interday were compared to similar results obtained by use of the UV-vis spectrophotometry technique, and the analytical results obtained in commercial formulations show that the voltammetric procedure using a hanging mercury drop electrode is suitable for analyzing haloperidol in complex commercial formulation samples.
- Ribeiro, Francisco W.P.,Soares, Janete E.S.,Becker, Helena,De Souza, Djenaine,De Lima-Neto, Pedro,Correia, Adriana N.
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scheme or table
p. 2036 - 2044
(2011/03/23)
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- Block of delayed-rectifier potassium channels by reduced haloperidol and related compounds in mouse cortical neurons
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Haloperidol is known as an antagonist of dopamine D2 receptors. However, it also blocks a variety of ion channels at concentrations above the therapeutic range. Reduced haloperidol (R-haloperidol), one of the main metabolites of haloperidol, has been repo
- Yang, Shi-Bing,Major, Felix,Tietze, Lutz F.,Rupnik, Marjan
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p. 352 - 362
(2007/10/03)
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- Reduction of drug ketones by dihydrodiol dehydrogenases, carbonyl reductase and aldehyde reductase of human liver
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In this study, we compared the enzymatic reduction of 10 drugs with a ketone group by homogeneous carbonyl reductase, aldehyde reductase and three dihydrodiol dehydrogenases of human liver cytosol. At least one and in some cases all of the three dihydrodi
- Ohara, Hirotami,Miyabe, Yoshiyuki,Deyashiki, Yoshihiro,Matsuura, Kazuya,Hara, Akira
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p. 221 - 227
(2007/10/03)
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- Phenylbutanol derivatives
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Butyrophenone derivatives having excellent psychotropic activity and represented by the formula, SPC1 Wherein A represents a single or double bond linkage; R1 represents a hydrogen atom or a C1 - C4 alkyl group; R2, which is present only in case A represents a single bond linkage, represents a hydrogen atom, or a hydroxyl, C1 - C4 alkyl, or C1 - C4 alkoxy group; R3 represents a hydrogen atom, or a piperidino, pyrrolidino, morpholino, furyl, thienyl, C1 - C4 alkylamino, benzylamino, unsubstituted or halogen-substituted phenyl group, etc.; and X represents a hydrogen or halogen atom, or a C1 - C4 alkyl, C1 - C4 alkoxy, or trifluoromethyl group, can be prepared by reducing a benzoylpropionamide derivative of the formula, SPC2 Wherein A, R1, R2, R3 and X have the same meanings as defined above, to a phenylbutanol derivative of the formula, SPC3
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