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PubMed1981

Synthesis and structure--activity relationships of selected tricyclic oxime O-ethers as potential anticholinergic agents.

Selected isomeric and nonisomeric oxime O-ether derivatives of thioxanthone oxime were synthesized and evaluated for anticholinergic activity. The oxime O-ethers were prepared via O-alkylation of the oximate anion with appropriate aminoaklyl halides. Separation and isolation of the structural isomers were accomplished through dry-column chromatography. The racemic alpha-methyl isomer was resolved via formation of tartrate diastereomers, which were subsequently isolated. All synthesized compounds exhibited significant antimuscarinic activity. A comparison of the antimuscarinic activities of these compounds revealed that the racemic alpha-methyl isomer was the most potent and that the racemic beta-methyl isomer was the least potent. Structure-activity relationships among the oxime O-ether derivatives synthesized are discussed.

Animals↗
PubMed1995

Oxime derivatives of the intermediary oncostatic metabolites of cyclophosphamide and ifosfamide: synthesis and deuterium labeling for applications to metabolite quantification.

There is ongoing interest in the selective, quantitative analysis of the cyclophosphamide metabolites 4-hydroxycyclophosphamide (2a) and aldophosphamide (3a) because these tautomers are generally believed to play a key role in oncostatic selectivity and metabolite transport. O-(2,3,4,5,6-Pentafluorobenzyl)hydroxylamine (C6F5CH2ONH2, 1 equiv) provided for the complete conversion (by 31P NMR, 60% reaction within 15 min at 20 degrees C) of 2a/3a (17 mM in H2O/CH3OH) to E/Z-aldophosphamide O-(2,3,4,5,6-pentafluorobenzyl)oxime [C6F5CH2ON = CHCH2CH2OP-(O)(NH2)N(CH2CH2Cl)2; E:Z = 54:46 (+/- 3% average deviation)]. Under these conditions, the oxime exhibited little (6%) decomposition over 3 weeks. Parallel studies showed that 4-hydroxyifosfamide/aldoifosfamide reacted completely to give the analogous aldoifosfamide oxime [C6F5CH2ON = CHCH2CH2OP(O)(NHCH2CH2Cl)2; E:Z = 52:48 (+/- 1% average deviation)] with 50% reaction within 15 min at 20 degrees C with no product decomposition over 3 weeks. In aqueous methanol and with 2 equiv C6F5CH2ONH2, clinically useful 4-hydroperoxycyclophosphamide (10 mM; tau 1/2 = 10 min, 37 degrees C) and its isomer 4-hydroperoxyifosfamide (10 mM; tau 1/2 = 25 min, 20 degrees C) underwent complete conversion to the corresponding aldehyde oximes. Each oxime was synthesized with deuterium in the chloroethyl moieties for use as internal standards in GC/MS applications.

Cyclophosphamide↗
PubMed2004

A(1,3)-strain mediated epimerization of 2e,3e,5e,6e-tetraarylpiperidin-4-one oximes.

A series of tri- and tetraarylpiperidin-4-one oximes were synthesized from 2e,3e,6e-tri- and 2e,3e,5e,6e-tetraarylpiperidin-4-ones, respectively. In the case of the latter compounds, oximation is accompanied by epimerization at C-5 to avoid the A(1,3)-strain between the oxime OH group and the 5e-aryl ring of the initially formed oxime resulting in 2e,3e,5a,6e-tetraarylpiperidin-4-one oximes. 1H, 13C and 2D NMR spectroscopic data were employed to characterize and investigate the stereochemistry of these compounds.

Anti-Infective Agents↗
PubMed1993

Comparison of several oximes on reactivation of soman-inhibited blood, brain and tissue cholinesterase activity in rats.

The ability of three oximes, HI-6, MMB-4 and ICD-467, to reactivate cholinesterase (ChE) inhibited by the organophosphorus compound soman was compared in blood (plasma and erythrocytes), brain regions (including spinal cord) and peripheral tissues of rats. Animals were intoxicated with soman (100 micrograms/kg, SC; equivalent to 0.9 x LD50 dose) and treated 1 min later with one of these oximes (100 or 200 mumol/kg, IM). Toxic sign scores and total tissue ChE activities were determined 30 min later. Soman markedly inhibited ChE activity in blood (93-96%), brain regions (ranging from 78% to 95%), and all peripheral tissues (ranging from 48.9% to 99.8%) except liver (11.9%). In blood, treatment with HI-6 or ICD-467 resulted in significant reactivation of soman-inhibited ChE. In contrast, MMB-4 was completely ineffective. HI-6 and ICD-467 were equally effective at the high dose. At the low dose ICD-467 treatment resulted in significantly higher plasma ChE than HI-6 treatment, whereas HI-6 treatment resulted in higher erythrocyte ChE than ICD-467 treatment. However, none of these three oximes reactivated or protected soman-inhibited ChE in the brain. In all peripheral tissues (except liver) studied, MMB-4 was not effective. HI-6 reactivated soman-inhibited ChE in all tissues except lung, heart, and skeletal muscle. ICD-467 was highly effective in reactivating ChE in all tissues and afforded a complete recovery of ChE to control levels in intercostal muscle and salivary gland. Oxime treatments did not modify the toxic scores produced by soman. However, treatment with the high dose (200 mumol/kg) of ICD-467 depressed respiration and two of the six rats died in 10 min. These observations indicate that MMB-4 is completely ineffective in protecting and/or reactivating soman-inhibited ChE, HI-6 is an effective ChE reactivator as reported earlier in rats and other species, and the imidazolium oxime ICD-467 is a powerful reactivator of soman-inhibited ChE; however, its toxic interactions with soman may not be related to tissue ChE levels.

Animals↗
PubMed1994

In vitro oxime-induced reactivation of various molecular forms of soman-inhibited acetylcholinesterase in striated muscle from rat, monkey and human.

The purpose of this study was to compare the in vitro reactivation of the various molecular forms of soman-inhibited acetylcholinesterase by oximes such as HI-6, toxogonin and PAM, in striated muscle tissue from three species-rat, monkey and human. To simulate the various in vivo conditions the oxime was present either 5 min before and after (Pre-Post) or 5 min after (Post) exposure to the nerve agent soman. In the Pre-Post mode the oxime effects would result from a combination of not only shielding of acetylcholinesterase from soman inhibition but also from immediate reactivation of soman-inhibited acetylcholinesterase. In the Post experimental group the increase in soman-inhibited acetylcholinesterase activity was due to reactivation. HI-6 (Pre-Post) increased significantly the activity of soman-inhibited acetylcholinesterase in the rat, human and monkey muscle. HI-6 (Post) was a highly effective reactivator of soman-inhibited acetylcholinesterase in the rat muscle and moderately so in the human and monkey muscle. Toxogonin (Pre-Post) and toxogonin (Post) were effective in increasing soman-inhibited acetylcholinesterase activity in rat muscle but were relatively ineffective in the human and monkey muscle. PAM (Pre-Post) and PAM (Post) were ineffective in increasing soman-inhibited acetylcholinesterase activity in muscle from all species examined. Effectiveness of oxime-induced reactivation of soman-inhibited acetylcholinesterase could be estimated from the total acetylcholinesterase activity which appears to reflect the results found with the individual molecular forms of acetylcholinesterase. In addition, SAD-128, a non-oxime bispyridinium compound, appeared to enhance significantly the HI-6 induced reactivation of soman-inhibited acetylcholinesterase in human but not rat striated muscle.

Acetylcholinesterase↗
PubMed1995

Cardiorespiratory function in nerve agent poisoned and oxime + atropine treated guinea-pigs: effect of pyridostigmine pretreatment.

The effect of pyridostigmine pretreatment on the efficacy of oxime + atropine treatment in sarin and VX poisoning was investigated in a guinea-pig model with on-line monitoring of respiratory and circulatory parameters. The carotid artery, jugular vein and trachea were cannulated in female urethane-anesthetized Pirbright-white guinea-pigs. After baseline measurements the animals received pyridostigmine (PYR, 0.05 mumol/kg, i.v.), 30 min later sarin (100 or 200 micrograms/kg = 5 or 10 x LD50, i.v.) or VX (45 or 90 micrograms/kg = 10 or 20 x LD50, i.v.), followed 2 min later by atropine (10 mg/kg, i.v.) plus HI 6 or HLö 7 (30 mumol/kg each, i.v.). Sixty-minute survival time and rate and respiratory and circulatory parameters were recorded. Diaphragm acetylcholinesterase (AChE) activity was determined spectrophotometrically. Identical groups without PYR were included for comparison. With regard to survival time and rate, PYR pretreatment slightly improved the efficacy of HI 6 plus atropine in sarin 5 x LD50 poisoned animals, reduced the efficacy of oxime + atropine treatment in the other sarin groups and had no effect in VX poisoning. Compared to non-pretreated oxime + atropine groups, PYR slightly improved respiratory function in sarin and in VX poisoning (only HI 6). PYR did not affect circulatory function in VX poisoning but reduced circulatory parameters in sarin poisoning to varying extent's. The oxime efficacy in reactivating diaphragm AChE decreased in the order sarin > VX without significant differences between pretreated and non-pretreated groups. The data suggest that pyridostigmine pretreatment does not enhance the efficacy of oxime + atropine in sarin or VX poisoning.

Animals↗
PubMed1997

Antidotal efficacy of quinuclidinium oximes against soman poisoning.

The efficiency of newly synthesized oxime derivatives of quinuclidinium were tested in vitro on soman inhibited acetylcholinesterase (AChE) of human erythrocytes and in vivo using soman poisoned mice. For this purpose, the inhibitory power of oximes (IC50), acute toxicity (LD50) as well as reactivating and protective capacities with respect to soman-inhibited AChE were determined for each of the oximes. All oximes tested were ineffective in vitro but protected mice very efficiently (BM-1 protects against 4LD50 of soman). The results indicate that the in vivo effectiveness of quinuclidinium oximes against soman poisoning may not be related to reactivation or protection of AChE but rather to some other mechanism of the cholinergic system.

Acetylcholinesterase↗
PubMed2002

Determination of 6-oxo-morphinans, as the oximes, by difference circular dichroism spectroscopy.

A negative Cotton effect is observed in the circular dichroism (CD) spectra of 6-oxo-morphinans in the wavelength range of n-pi* electron transitions. 6-oxo-Morphinans can be transformed into oxime derivatives with hydroxylamine and after oxime formation the CD spectra are significantly different. Oxime formation was monitored by CD and by HPLC. It was established that under the experimental conditions used oxime formation was complete within 90 min. The method suggested for the determination of 6-oxo-morphinans is based on the considerable differences between the ellipticities before and after the oxime formation. The ellipticity difference varies linearly with concentration in the range 2 x 10(-5)-5 x 10(-4) mol L(-1) for the three 6-oxo-morphinans examined (oxycodone, hydrocodone, and 14-hydroxycodeinone). For hydrocodone the dependence is also linear in a lower concentration range (5 x 10(-6)-10(-4) mol L(-1)). The new difference CD spectroscopic method can be applied to the selective determination of 6-oxo-morphinans in bulk and dosage forms.

Circular Dichroism↗
PubMed1990

Evaluation of several oximes as reactivators of unaged soman-inhibited whole blood acetylcholinesterase in rabbits.

The antidotal benefit of oximes against organophosphorus (OP) anticholinesterase intoxication is thought to be due to reactivation of the OP-inhibited acetylcholinesterase (AChE). This study was conducted to determine whether the antidotal efficacy against soman by the oximes 2-hydroxyiminomethyl-3-methyl-1-[2-(3-methyl-3-nitrobutyl oxymethyl)]-imidazolium Cl (ICD 467) and 1,1'-methylenebis[4-(hydroxyiminomethyl) pyridinium] di-Cl (MMB-4) resulted, in part, from reactivation of the inhibited AChE. These oximes were tested in parallel with pralidoxime Cl (2-PAM) and 1-(2-hydroxyiminomethyl-1-pyridinio-3-(4-carbamoyl-1-pyridinio+ ++)-2-oxapropane di-Cl (HI-6). Rabbits were atropinized (8 mg/kg, i.m.) and intoxicated with soman (13 micrograms/kg, i.v.; 1.2 x LD50) 5 min later. Three minutes after soman, animals were treated with oxime (50, 100 or 150 mumol/kg, i.m.). Whole blood was collected from a catheter in the central artery of the ear just before soman, at 2 min after soman and at 2, 5, 10, 15, 30, and 60 min after oxime or vehicle for determination of AChE activity. Shortly thereafter, animals were anesthetized and exsanguinated with immediate flushing using heparinized saline. AChE activity was also determined on the cortex, medulla-pons and diaphragm to assess central and peripheral reactivation. Treatment with HI-6 or MMB-4 (50 mumol/kg, i.m.) resulted in significant (P less than 0.05) reactivation of soman-inhibited whole blood AChE and diaphragm cholinesterase (ChE), but not brain AChE. In contrast, 2-PAM was completely ineffective in reactivating soman-inhibited AChE. HI-6 was significantly better than MMB-4 in reactivating blood AChE; they were essentially equal against soman-inhibited diaphragm ChE. Three animals exposed to soman and treated with ICD 467 died within 15 min. When animals not exposed to soman were treated with ICD 467 (25 mumol/kg, i.m.), whole blood AChE activity was depressed by 60% within 5-10 min after treatment. Furthermore, ICD 467 failed to reactivate significantly unaged soman-inhibited erythrocyte AChE, in vitro. These observations indicate that ICD 467 would be contraindicated as a therapy for anti-ChE intoxication and that the efficacy of HI-6 or MMB-4 can be explained, in part, by reactivation of soman-inhibited AChE.

Acetylcholinesterase↗
PubMed1981

The efficacy of some bis-pyridinium oximes as antidotes to soman in isolated muscles of several species including man.

Previous results had shown that bis-pyridinium oximes, particularly HI-6 are quite effective therapeutically in soman-poisoned rats and mice in vivo and in the rat diaphragm preparation in vitro. The aim of the present study was to investigate the efficacy of bis-pyridinium oximes on soman-inhibited neuromuscular transmission in muscle preparations from several species including man. The muscles tested were preparations of rat diaphragm and intercostal muscle, guinea-pig diaphragm, dog external intercostal muscle and human external interscotal muscle. These muscles were stimulated indirectly with field stimulation. With a few exceptions the preparations were exposed to soman for 2.5 or 15 min. In some cases different exposure times were employed or the organophosphate sarin was administered instead of its analogue soman. After the degree of inhibition of neuromuscular transmission had been established, oximes were added to the bath fluid. After washout 15 min later, recovery of neuromuscular transmission was tested. Subsequently, a second dose of soman was administered to investigate whether the recovery observed had been caused by cholinesterase reactivation. The results of these experiments indicate that the oximes tested, mostly HI-6, were quite effective as soman antidotes in muscle preparations of rats, guinea-pigs and dogs. In the human preparation while these oximes were quite effective after sarin intoxication they were essentially without effect against soman.

Adult↗
PubMed1994

Rate constants of carbamylation and decarbamylation of acetylcholinesterase for physostigmine and carbaryl in the presence of an oxime.

Membrane-bound bovine erythrocyte acetylcholinesterase was inhibited with physostigmine or carbaryl, and the rate constants of carbamylation and decarbamylation were determined from the proportion of inhibited acetylcholinesterase in the steady state, and the rate of approach to the steady state. The oximes 2-PAM, HI-6, HS-6, TMB-4 and toxogonin, at 0.1 mM, all decreased the rate of carbamylation by physostigmine, but increased the rate of carbamylation by carbaryl. TMB-4 and toxogonin were the most effective oximes in potentiating carbamylation by carbaryl, with an enhancement of the second-order rate constant of 54- and 17-fold respectively. The greatest reduction in the rate constant for carbamylation by physostigmine (3.7-fold) was caused by HI-6. HS-6 and HI-6 increased the rate of decarbamylation, while 2-PAM reduced the rate of decarbamylation if physostigmine was the carbamate. 2-PAM and HI-6 were also studied with soluble bovine erythrocyte acetylcholinesterase, and similar results were obtained. The results extend those in a recent report by other authors who studied the half-life of carbamylation for acetylcholinesterase and butyrylcholinesterase in an attempt to understand the mechanism by which oximes increase the toxicity of carbaryl in vivo. These authors proposed binding of the oximes to an allosteric site on the enzyme. While not discounting this possibility, the present results, taken with other reports in the literature, suggest that binding of the oximes to the anionic subsite of the active site of the enzyme is also feasible. The present results also offer an explanation for another recent report, in which anomalous results were presented for decarbamylation of physostigmine-inhibited and carbaryl-inhibited erythrocyte acetylcholinesterase in the presence of 2-PAM or HI-6.

Acetylcholinesterase↗
PubMed1989

Sulfation of mono- and diaryl oximes by aryl sulfotransferase isozymes.

Aryl sulfotransferases (3'-phosphoadenylsulfate:phenol sulfotransferase, EC 2.8.2.1) catalyze the sulfonation of a wide variety of hydroxyl-containing substrates, including numerous xenobiotics. The chemical diversity of aryl sulfotransferase substrates is in part attributable to the presence of multiple isozymes, each of which has broad substrate specificity. Of the aryl sulfotransferase isozymes in rat liver cytosol, two (designated isozymes I and II) have previously been shown to sulfonate phenolic compounds exclusively and, moreover, have very similar substrate specificity patterns. The recently reported unusually efficient, rapid isozyme I-catalyzed sulfonation of 9-fluorenone oxime (Mangold, J.B., Mangold, B.L.K. and Spina, A. (1986) Biochim. Biophys. Acta 874, 37-43) was therefore unexpected and suggested that aryl oximes may represent a useful class of model compounds to probe isozymic differences in substrate steric and electronic requirements. In the present study, several mono- and diaryl oximes have been prepared and tested as potential substrates for partially purified aryl sulfotransferases I and II from rat liver cytosol. The results indicate that steric factors, specifically planarity and hydroxyl group position, appear to be important requirements for enzyme-catalyzed sulfonation. In addition, although isozymes I and II had comparable activity with diaryl oximes, some striking differences in the ability of these two isozymes to sulfonate both substituted and unsubstituted monoaryl oximes were observed. This dissimilarity is consistent with distinct differences in the active sites of these isozymes.

Arylsulfotransferase↗
PubMed1989

Cold exposure decreases the effectiveness of atropine-oxime treatment in organophosphate intoxication in rats and mice.

1. The effect of cold environment on the acute toxicity of organophosphates (OP), without and with atropine-oxime treatment, was studied in rats and mice by exposing them to +5 and -5 degrees C temperature. The tested OPs and oximes (given intraperitoneally) were diisopropylfluorophosphate (DFP), isopropyl methylphosphonofluoridate (sarin) and dichlorovinyl phosphate (DDVP), pralidoxime (PAM) and obidoxime. 2. An exposure to low environmental temperature decreased the effectiveness of atropine-oxime therapy in OP poisoned rats and mice, evaluated by means of acute LD50 values. 3. The lowering of environmental temperature did not influence the ability of PAM to reactivate tissue cholinesterase in rats intoxicated by 0.5 x LD50 doses of DFP. 4. The acute toxicity of atropine and oximes was not affected by cold environment in rats, but in mice it was increased by 1.1-2.1 times. 5. The decrease in the effectiveness of atropine-oxime therapy at cold environment may be explained by the observation that the cold temperature sensitizes the animals to the inhibition of brain acetylcholinesterase by OP.

Animals↗
PubMed2004

Relaxant effect of oxime derivatives in isolated rat aorta: role of nitric oxide (NO) formation in smooth muscle.

Various oxime derivatives were evaluated as nitric oxide (NO) donors in arteries. Relaxation of rat aortic rings was used for bioassay of NO production, and electron paramagnetic resonance spectroscopy for demonstration of NO elevation. In rings with or without endothelium or adventitia, hydroxyguanidine and hydroxyurea were almost inactive, whereas formamidoxime, acetaldoxime, acetone oxime, acetohydroxamic acid and formaldoxime elicited relaxation. Active compounds increased NO levels in endothelium-denuded rings. Formaldoxime was the most potent agent for both relaxation and NO elevation in aortic rings, and it also increased NO in human aortic smooth muscle cells. In endothelium-denuded rings, relaxation was inhibited by a NO scavenger (2-phenyl-4,4,5,5-tetramethyl-imidazoline-1-oxyl-3-oxide) and by inhibitors of soluble guanylyl-cyclase (1H[1,2,4,]oxadiazolo[4,3-a]quinoxalin-1-one) or cyclic GMP-dependent protein kinases (Rp-8-bromo cyclic GMP monophosphorothioate). Neither N(omega)-nitro-l-arginine methylester (a NO synthases inhibitor) nor proadifen (a cytochrome P450 inhibitor) decreased the effect of oxime derivatives. However, 7-ethoxyresorufin (7-ER, an inhibitor of P4501A(1) which can also inhibit various NADPH-dependent reductases) abolished the relaxant effect of these compounds, without affecting the one of glyceryl trinitrate (GTN) or 2-(N,N-diethylamino)-diazenolate-2-oxide. 7-ER also abolished formaldoxime-induced NO increase in aortic rings. In rings tolerant to GTN, formaldoxime-induced relaxation and NO elevation were not different from those obtained in control rings. In conclusion, some oxime derivatives release NO by 7-ER-sensitive pathways in aortic smooth muscle, thus eliciting vasorelaxation. Pathways of NO formation are likely distinct from NO synthases and from those responsible for GTN biotransformation. Oxime derivatives could be useful for NO delivery in arteries in which endothelial NO synthase activity is impaired.

Animals↗
PubMed2003

Synthesis of two and antibacterial activity of one novel oxime ether derivatives of erythromycin A.

The synthesis of novel erythromycin A 9-O-(2-ethenesulfony-ethyl)-oxime and erythromycin A 9-O-(3-oxo-butyl)-oxime from erythromycin A (EA) by the Michael reaction is described and to describe the effects of transformation of ketone in position 9 of EA to an oxime ether. This transformation occurred in a single step without protecting of any functional moiety of erythromycin oxime and zero waste manner in good yield. The antibacterial screen of EA 9-O-(2-ethenesulfony-ethyl)-oxime is also reported.

Anti-Bacterial Agents↗
PubMed1991

The role of carboxylesterase in species variation of oxime protection against soman.

Oxime protection against soman, a highly toxic anticholinesterase agent, was examined in mice and guinea pigs. The maximal protection produced by the oximes PAM and HI-6 varied as much as 6-fold between these species. Since endogenous carboxylesterase (CaE) is known to be an important determinant of species variation in soman toxicity, the protection of PAM and HI-6 against soman was also measured in animals whose endogenous CaE was inhibited with cresylbenzodioxaphosphorin oxide. In CaE-inhibited animals the soman LD50 values were similar in unprotected mice and guinea pigs (10.2 vs. 12.2 micrograms/kg) and oxime-protected mice and guinea pigs (38.1 vs. 40.3 micrograms/kg for PAM; 159 vs. 151 micrograms/kg for HI-6). The levels of oxime protection observed in CaE-inhibited animals agreed with previous experiments in other species that have no endogenous plasma CaE. The 4-5 times greater in vivo protection against soman of HI-6 vs. PAM in CaE-inhibited animals correlated with in vitro experiments in which HI-6 produced 3-5 times more oxime reactivation of soman-inhibited AChE than PAM.

Animals↗
PubMed1988

Sulfur derivatives of 2-oxopropanal oxime as reactivators of organophosphate-inhibited acetylcholinesterase in vitro: synthesis and structure-reactivity relationships.

We have prepared four new oximes, 1b-e, which conform to the general structure RCH2COCH = NOH where R = CH3S, CH3SO, CH3SO2, and (CH3)2S+, respectively, and have the same E configuration as the parent 2-oxopropanal oxime 1a (R = H, MINA). The pKa values range from 6.54 (1e) to 8.16 (1b), as compared with 8.30 for 1a. Rates of reaction (kappa 1) with 4-nitrophenyl acetate indicate that the oximate anions have a much higher nucleophilicity than common oxyanions of similar basicities: the alpha effects measured for 1a-e are of the order of 200-250. The abilities of 1b-e to reactivate acetylcholinesterase (AChE) inhibited by organophosphates have been evaluated. In vitro experiments reveal a significant reactivation potency of 1b-e against VX-, sarin-, and paraoxon-inhibited immobilized eel AChE. The highly lipophilic methylthio oxime 1b (log P greater than 1) is intrinsically (kappa 2) 3 times more reactive than the more basic MINA (log P less than 1). The sulfonium oxime 1e is a potent reactivator against paraoxon. Interestingly, both 1b and 1e have a low toxicity and they exhibit a significant antidotal effect at a relative low dose against paraoxon in rats.

Acetylcholinesterase↗
PubMed2003

Orally active oxime derivatives of the dopaminergic prodrug 6-(N,N-di-n-propylamino)-3,4,5,6,7,8-hexahydro-2H-naphthalen-1-one. Synthesis and pharmacological activity.

A series of racemic and enantiomerically pure oxime derivatives of the potential anti-Parkinson prodrug 6-(N,N-di-n-propylamino)-3,4,5,6,7,8-hexahydro-2H-naphthalen-1-one (1) were synthesized and pharmacologically evaluated. The oximes induced rotational behavior in the Ungerstedt rat rotation model for Parkinson's disease after oral administration. Especially the unsubstituted oxime ((-)-3) and the acetyl-oxime ((-)-10) induced a pronounced and long lasting effect. In this model, large individual differences were observed in responsiveness to treatment between rats. Though less potent than the parent prodrug, the oxime derivatives of (+/-)-1 and (-)-1 can be orally active, acting as cascade prodrugs.

Administration, Oral↗