Effects Of Enantiomers Research Articles

Enantioselectivity in the Ecotoxicity of Amphetamine Using Daphnia magna as the Aquatic Model Organism: Morphophysiological, Behavioral, Reproductive and Biochemical Parameters.

Amphetamine (AMP) is a chiral psychoactive substance that exhibits enantioselectivity in its pharmacological properties. It has been detected in wastewaters and surface waters and can occur as enantiomeric mixtures, but little is known about its environmental risk and potential enantioselective toxicity to aquatic organisms. Our study aimed to target enantioselectivity in AMP toxicity to the freshwater invertebrate Daphnia magna. Daphnids were subchronically exposed to the racemate (rac-AMP: 0.1, 1.0, and 10 µg/L) and pure enantiomers, (R)-AMP and (S)-AMP (0.1, and 1.0 µg/L, respectively), for 8 days. Morphophysiological, swimming behavior, reproductive and biochemical variables were evaluated during critical life stages (juveniles vs. adults). Some responses were context-dependent and often enantioselective, varying between racemate and enantiomers and across the life stage of the organisms. Overall, rac-AMP stimulated D. magna growth, decreased heart rate and area, affected behavior, and stimulated reproduction. The effect of enantiomers was totally or partially concordant with rac-AMP, except for swimming behavior and reproduction. Enantioselectivity was observed for body size, number of eggs/daphnia, and heart rate (steeper decrease caused by (R)-AMP on day 3). Changes in biochemical parameters were also observed: AMP caused a significant decrease in catalase activity as racemate or pure enantiomers, whereas a decrease in acetylcholinesterase activity was found only for rac-AMP. Evidence for oxidative stress was contradictory, although both enantiomers caused a significant decrease in reactive oxygen species (unlike rac-AMP). Overall, these results show that AMP can interfere in an enantioselective way with aquatic organisms at low concentrations (e.g., 0.1 µg/L), demonstrating the relevance of this kind of study to an accurate environmental risk assessment regarding medium- to long-term exposure to this psychoactive drug. Environ Toxicol Chem 2023;00:1-13. © 2023 SETAC.

Distinct cognitive and discriminative stimulus effects of ketamine enantiomers in rats

Although (S)-ketamine was approved for use in treatment-resistant depression in 2019, new preclinical findings suggest that (R)-ketamine might produce better efficacy and tolerability relative to (S)-ketamine. Here we evaluated the effects of (R)-, (S)-, and (R,S)-ketamine on executive functions as measured in the attentional set shifting task (ASST) and on their discriminative stimulus effects in rats. Earlier data demonstrated that cognitive flexibility is compromised by (R,S)-ketamine, but the effects of enantiomers in rats are unknown. Separate cohorts of rats were tested in ASST and trained to discriminate either (R,S)-ketamine, (S)-ketamine, or (R)-ketamine (all at 10 mg/kg) from saline; in order to maintain the discrimination, a higher (R)-ketamine dose (17.5 mg/kg) was subsequently instituted. In ASST, all three forms increased the trials to criterion measure at reversal learning and extra-dimensional set-shifting phases. However, in contrast to (R)- and (S)-ketamine, (R,S)-ketamine prolonged the mean time to complete a single trial during early stages, suggesting increased reaction time, and/or unspecific side-effects related to motor or motivational impairments. In the drug discriminations, all rats acquired their respective discriminations between drug and saline. In (R,S)-ketamine-trained rats, (R)-ketamine and (S)-ketamine only partially substituted for the training dose of (R,S)-ketamine. Further, (R)-ketamine did not fully substitute in rats trained to (S)-ketamine. The data suggest more serious cognitive deficits produced by (R,S)-ketamine than its enantiomers. Furthermore, (R,S)-ketamine and its isomers share overlapping but not isomorphic discriminative stimulus effects predicting distinct subjective responses to (R)- vs. (S)-ketamine in humans.

Optical Stereoisomers of Geometric Isomers of the Octahedral Complex TiF4[Ph2P(O)CH2CH(OH)Me)]2 in CH2Cl2

Some peculiarities of the effect of enantiomers of the monodentate ligand on the stereoisomerism of the mixed octahedral tetrafluoride complexes of d0-transition metals are established by the 19F{1Н} and 31Р{1Н} NMR methods for the complex formation of TiF4 with Ph2P(O)CH2CH(OH)Me (L) having the asymmetric carbon atom in the aliphatic hydrocarbon radical and being a racemic mixture of enantiomers in СН2Сl2. The compositions of the complexes formed in solutions are determined. The conclusion about the relative stereochemical configuration of the chiral and meso-stereoisomers of the geometric isomers of the TiF4L2 octahedral complex is based on an analysis of the 19F NMR spectra using the heterotropic concept.

Stereoisomerism of Octahedral Titanium cis-Tetrafluoro Complexes with Ph2P(O)CH2CH(OH)Me Enantiomers According to 19F NMR Data

Effect of enantiomers of a monodentate ligand on the stereoisomerism of mixed octahedral cis-tetrafluoro complexes of d0 transition metals has been studied by 19F{1H} and 31P{1H} NMR by the example of TiF4 complexation in CH2Cl2 with Ph2P(O)CH2CH(OH)Me (L) containing asymmetric carbon atom in the aliphatic hydrocarbon group that constitutes a racemic mixture of enantiomers. Composition of complexes formed in solution has been determined, conclusion has been drawn on the relative stereochemical configuration of the chiral and meso stereoisomers of octahedral complex cis-TiF4L2 on the basis of analysis of 19F NMR spectra, using the heterotropism concept.

What one hand giveth the other taketh away: some unpredicted effects of enantiomers in psychopharmacology

It is well known that many medicines are a mixture of two enantiomers, or mirror-image molecules. Two enantiomers occur when a molecule has a single chiral centre and the two mirror images, called S or L (left handed) and R or D (right handed), are usually found in equal amounts in the parent (racemic) mixture. While for many compounds used in clinical practice the active moiety is found in one of the two enantiomers with the other being seen as an unnecessary and redundant component of the racemic mixture, the difference between enantiomers can mean a difference between therapeutic and adverse effects, as well as in beneficial pharmacological effect and potency.

Validation of an in vitro teratology system using chiral substances: stereoselective teratogenicity of 4-yn-valproic acid in cultured mouse embryos.

In vitro systems are important for toxicity testing as well as for investigating the mechanism of action of xenobiotics. The validation of such in vitro systems is often incomplete and extrapolation to the in vivo situation is equivocal. In the present study, we studied the effects of enantiomers of an analogue of the antiepileptic drug valproic acid (VPA): R(+)- and S(-)-4-yn-VPA (R- and S-2-n-propyl-4-pentynoic acid), which have previously been shown to induce selective teratogenicity in mice after in vivo administration, in mouse whole-embryo culture (WEC). Aqueous solutions of the sodium salts of the pure R- and S-enantiomers as well as R,S-4-yn-VPA (racemic mixture) or VPA itself were added to the culture medium at 0, 0.075, 0.15, 0.3, 0.6, or 1.2 mmol/liter and embryos were evaluated 24 hr later. The S-4-yn-VPA enantiomer induced clear concentration-dependent dysmorphogenesis that was evident even at the lowest concentration. The primary anomalies were neural tube defects, erratic neural seams, blisters, and rotational defects. Embryolethality was observed at 1.2 mmol/liter. The R-4-yn-VPA enantiomer was neither embryotoxic nor dysmorphogenic at any tested concentration. The lack of biological activity over 24 hr in WEC with the R-enantiomer suggests also that, as previously shown in vivo, there was no racemization of this isomer to the more active S-enantiomer. The racemic mixture of R and S isomers appeared to be slightly more embryolethal and dysmorphogenic than VPA. Overall, the potency of the S-enantiomer was approximately four times that of VPA. Therefore, the rank order of the four chemicals tested was S(-) >> S(-), R(+) > VPA >>> R(+), which is in agreement with the effects observed in in vivo exposed mice. These data demonstrate a direct stereoselective effect of these compounds on the embryo. This is the first illustration of the stereoselectivity of a xenobiotic in the WEC in vitro test system. Pure and stable enantiomers, which induce stereoselective toxicity in vivo, are demonstrated to be valuable for validation of this in vitro system.

Reinforcing effects of enantiomers of N,N-dimethylamphetamine in squirrel monkeys

Reinforcing effects of the (+)- and (-)-enantiomers of N,N-dimethylamphetamine, a drug that is abused in humans, were studied in squirrel monkeys (Siamiri sciureus) trained under schedules of intermittent cocaine reinforcement. During training, each 30th response produced an injection of cocaine (fixed-ratio schedule), which was followed by a 1-min period during which lights were out and responses had no scheduled consequences (timeout). Sessions in which cocaine injections were scheduled alternated in an irregular sequence with sessions in which saline injections were scheduled. After training, response rates were well maintained by cocaine (response rates approximated 1.4 responses per second) but occurred relatively infrequently during sessions in which saline was injected (response rates approximated 0.3 responses per second). Doses of 10 to 56 micrograms/kg/injection of (+)-N,N-dimethylamphetamine maintained rates of responding significantly higher than those maintained by saline. The (-)-enantiomer did not maintain rates of responding that were higher than those maintained by saline when tested at doses up to 100 micrograms/kg/injection. These findings support previous results indicating that N,N-dimethylamphetamine will function as a reinforcer in laboratory animals. Further, they suggest that the significant reinforcing activity of this drug is restricted to the (+)-enantiomer.

Effect of enantiomers of propranolol on desipramine-induced anti-immobility in the forced swimming test in the rat

The effect of d- and l-enantiomers of propranolol on desipramine-induced anti-immobility effects and on brain desipramine levels was studied in the rat. Intraperitoneal propranolol and desipramine were administered three times, 25, 6, 2 and 24, 5, 1 h respectively, before the test. It was found that l-propranolol but not d-propranolol, at the same doses (2.5 and 5 mg/kg), antagonized 20 mg/kg desipramine without altering desipramine brain levels. It is suggested that blockade of beta-adrenergic receptors rather than membrane-stabilizing or pharmacokinetic effects is responsible for the antagonism of propranolol toward desipramine.

Asymmetric amplifying phenomena in enantioselective addition of diethylzinc to benzaldehyde

BACKGROUND In 1986, Puchot et al. established rigorously that the earlier proposal of Wynberg and Feringa concerning the effect of enantiomers on one another had general validity. Puchot et al. showed experimentally that the general assumption, namely, that products could never have an e.e. greater than that of the chiral auxiliary (catalyst, modifier, etc), was invalid. The basis for this apparent anomaly, as was discussed theoretically in 1976, is the possible association of enantiomeric catalyst molecules with new (better and worse) catalyst properties. Early proof of association phenomena of chiral molecules to form diastereomers (particularly, chiral hydroxy amines) had been obtained by a classic experiment of Williams et al. The latter showed that in a solution of enantiomerically impure quinine, distinct NMR absorptions could be detected for the ( + ) ( + ), ( – ) ( – ), and ( + ) ( – ) “dimeric complexes” in achiral solvents. It is, of course, not surprising (except in the sense that we did not recognize this much earlier!) that an efficient chiral catalyst, which by its very behavior must complex strongly with the achiral substrates, also complexes with itself. It should also come as no surprise, therefore, that such associative dimers (or trimers, etc.) might show different (better or worse) catalytic properties.

Different effects of enantiomers of tetrahydropalmatine on dopaminergic system.

Tetrahydropalmatine (THP) has two enantiomers with different effects on the brain dopaminergic system. Using [3H]spiperone for DA receptor binding assay, it was found that l-THP had an affinity to DA receptors (Ki = 0.2 microM). Neither d-THP nor reserpine showed such an effect even at concentrations higher than 100 or 1000 microM. Based on the fact that the presynaptic DA receptors take part in feed-back regulation on tyrosine hydroxylase activity, DOPA accumulation could be observed in rat striatum after injection of benserazide. A small dose of l-THP (2.5, 5, 10 mg/kg, ip.) caused an elevation of DOPA level by 49-282% versus the control value, and could reverse the decrease of DOPA level induced by apomorphine, a DA receptor agonist. On the contrary, d-THP displayed a biphasic effect on DOPA level, slight decrement (26-37%) at 10 and 25 mg/kg, naught at 50 mg/kg, and a 91% increment at 100 mk/kg, which was less than that of l-THP at 5 mg/kg. Moreover, measured by pulse voltammetry, DOPAC level in the striatum was raised by 88 or 190% at 2.5 or 10 mg/kg respectively. By means of spectrofluophotometry, l-THP at 50-100 mg/kg reduced DA level by 24-26%. However, the DA content reduction induced by d-THP is much more dose-dependent. At a small dose (10 mg/kg), d-THP predominantly reduced the DA level but left 5-HT and NA level unaffected. It caused an 80% reduction of DA at 100 mg/kg. From the above findings, it might be concluded that l-THP is a DA receptor antagonist, while d-THP is probably a DA depletor.