Dissertations / Theses on the topic 'Enantiomeric effect'

Major depressive disorder (MDD) is a widespread psychiatric disorder that affects millions of people worldwide and is hypothesized to occur due to impairments in several neurotransmitter systems, including the monoaminergic and glutamatergic neurotransmitter systems. Antidepressant medications targeting multiple monoamine neurotransmitters have been shown to be effective for the treatment of depression. Racemic amisulpride is an atypical antipsychotic that has been used at low doses to treat dysthymia, a mild form of depression, and functions as an antagonist at DA2/3, 5-HT2B, and 5-HT7 receptors. Recent preclinical studies have suggested that the S(+) isomer may be more critical for amisulpride’s antidepressant-like effects; however, this interpretation has not been fully characterized in comparison to the R(-) isomer. The glutamatergic system also has been shown to play a critical role in alleviating depression. Several studies have demonstrated that the noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist ketamine produces rapid and sustained antidepressant-like effects in clinical trials; however, few studies have examined the degree to which ketamine’s isomers contribute to antidepressant-like effects. Fully characterizing these differences in a preclinical model of depression may offer important insight into the role of these neurotransmitter systems on depression. The present study used a 72-sec differential-reinforcement-of-low-rate (DRL) task to assess the antidepressant-like effects of amisulpride, ketamine, and their isomers in mice. The DRL 72-sec task has shown to be a reliable and sensitive screen for drugs that possess antidepressant-like activity as reflected by an increase in the number of reinforcers, a decrease in the number of responses, and a right-ward shift in the interresponse time distributions (IRTs; i.e. the elapsed time between two successive responses). For comparison, the effects of the tricyclic antidepressant imipramine and the N-methyl-D-aspartate antagonist MK-801 as positive and negative controls, respectively, were determined. Consistent with previous findings, we hypothesized that amisulpride and S(-)-amisulpride, but not R(+)-amisulpride, would produce antidepressant-like effects, and all formulations of ketamine would produce antidepressant effects. Racemic amisulpride and S(-)-amisulpride, but not R(+)-amisulpride, produced an antidepressant-like effect, evidenced by a significant increase in the number of reinforcers and a significant decrease in the number of responses. Racemic ketamine and R(-)-ketamine significantly increased the number of reinforcers and decreased the number of responses, while S(+)-ketamine significantly increased the number of reinforcers, but did not decrease the number of responses (at the doses tested). Overall, these results indicate that the racemic formulations of amisulpride and ketamine, S(-)-amisulpride, and both ketamine isomers demonstrate antidepressant-like effects as assessed in the DRL task and may be useful in a clinical context. If either of the ketamine isomers can be shown to produce fewer psychotomimetic effects in humans, then the isomers may offer a significant clinical advantage over the parent compound ketamine. Regarding amisulpride, the present results demonstrate that the S(-) isomer, but not the R(+) isomer, possess antidepressant-like activity similar to racemic amisulpride.

On montre, qu'il est possible d'alkyler avec une bonne énantiosélectivité des énolates prochiraux au moyen d'agents électrophiles à nucléofuges chiraux dérivés du d(+)-glucose. La glycine est ainsi transformée en alanine avec excès énantiomère atteignant 75%. Mise en évidence du rôle des substituants R2 et R3 de l'imine dérivée de l'aminoacide. C'est ainsi qu'en encombrant la région syn de la base de Schiff, les excès énantiomères passent de 0 à 70%. De même des modifications de la structure de l'agent d'alkylation ont permis d'attribuer des centres d'asymétrie importants dans le phénomène de l'induction

Acid/base modifiers are sometimes used as additives in the elution on columns packed with amylose tris(3,5-dimethylphenylcarbamate) stationary phase to separate enantiomers. When modifiers are removed from the mobile phase, the stationary phase is affected in ways that are not understood because of the lack of systematic studies, making the scale-up of preparative separations difficult to predict. Once a column has been exposed to these modifiers, the selectivity of certain pairs of enantiomers may change, for the better or the worse. Numerous pairs of molecules affected by this phenomenon are listed in the literature. Five pairs of these molecules were chosen, the selectivity of which changes after an acidic or basic solutions has been percolated through the column. The selectivity of the ketoprofen, 4-chlorophenylalanine methyl and ethyl esters improves after a solution of ethanesulfonic acid is percolated through the column. The selectivity of the propranolol HCl and Troger’s base increases after a solution of diiospropylethylamine is percolated through the column. The selectivity of these the 4-chlorophenylalanine ethyl ester, propranolol and Troger's base enantiomers are inversely affected by percolation of the opposite acid/base solution. This residual change in certain enantiomeric separations has been named the Memory Effect. In contrast, trans-stilbene oxide (TSO) was used as a standard to determine the column's stability because no Memory Effect is observed for this separation (the retention, enantioselectivity, and resolution remain constant). Karl Fischer titrations showed that only slight changes in the mobile phase's water content occurred, and that the water to polymer repeat unit ratio is important. Analytical studies of the stationary phase suggest that slow protonation/deprotonation of water bounded to the carbamate moiety may be responsible for the Memory Effect. It has been shown that the Memory Effect can be minimized by percolating through the column a sufficiently concentrated solution of the appropriate acid or base. Thus, columns that were unreliable for method development, due to the Memory Effect, can now be used. As a result, the scale-up of separations can be predicted and successfully performed. Finally, a test was devised to determine if a column was under the influence of the Memory Effect.

The B3-adrenoceptor (B-AR) was first classified in 1984 in rat brown adipose tissue. The classification of this receptor in other tissues and species is hampered by the lack of selective B3-antagonists which, despite the identification of further classes of B3-agonist ligands, remains elusive. In this study, a series of novel B3-AR antagonist drugs were synthesised and their pharmacological profile in rat ileum investigated with the aim of increasing our understanding of the structural requirements of drug-receptor binding in B3-ARs. Analogues of iodocyanopindolol (ICYP) (17) and conformationally impaired analogues of BRL 37344 were identified as key synthetic targets.

ICYP and eleven analogues were synthesised from epoxide precursor (38). The pharmacological activity of these compounds was determined in a rat ileum preparation with tissue contraction solely due to the B3-AR. All ICYP analogues were active at the B3-AR. The pharmacological data revealed: (i) of the analogues tested, ICYP (17) and CYP (18) had the highest affinities at the B3-AR. This is in sharp contrast to the binding of ICYP (17) and CYP (18) at B1- and B2-ARs where ICYP (17) has a hundred fold higher affinity than CYP (18); and (ii) two pharmacological characteristics determined for the drugs, namely pD2 and the pKb, were significantly different for eight of the analogues studied. These drugs were partial agonists, and the discrepancy between pD2 and pKb values indicated binding to more than one receptor population.

Three hypotheses were proposed to explain this observation; (i) two different B3-ARs are present; (ii) the result is an enantiomeric effect; and (iii) the difference is a non-specific lipophilic effect.

Log P values for the series were determined using HPLC, and no correlation was found between Log P and pD2 or pKb values.

To examine the second hypothesis, both enantiomers of CYP (18) and bupranolol (8) were synthesised and their pharmacological activity investigated in rat ileum. All four enantiomers tested were antagonists at the B3-AR, with the receptor displaying stereoselectivity for the (S)-enantiomers, with (S)-CYP (18b) being the most potent B3-antagonist drug identified. Examination of the partial agonist activity of CYP and bupranolol enantiomers suggested that this effect was independent of the mechanism of B3-antagonism. The partial agonist effect was selective for (R)-CYP (18a) and non-selective for bupranolol. This result clearly defines (S)-CYP (18b) as a potent B3-AR antagonist and highlights structure-activity studies of CYP analogues as an important new source of information for the design of new classes of B3-antagonist drugs.

To further investigate the structure-function relationship being developed for B3-AR selective drugs the "extended conformation" hypothesis of Blin and co-workers was examined. These researchers proposed that the discrepancies observed between the B3-AR activity, and the B1/B2-AR activity of known agonist and antagonist drugs resulted from the ability of B3-agonist drugs to adopt an extended conformation at the B3-AR. To investigate this postulate, conformationally impaired analogues of the B3-AR agonist BRL 37344 (6) were targeted for synthesis. Allylic amine (112) was identified as a key precursor for conformationally impaired BRL 37344 analogues and was synthesised with solely (E) geometry from (d)-Bocalinal (109) and 4-methoxy benzylphosphonium chloride (111). Progress in the synthesis of other subtargets is described.

碩士
國立中正大學
化學研究所
92
A high proportion of agrochemicals are chiral compounds. Since stereoisomers often show different biological and physio- logical properties, the biological and metabolic responses to these compounds and their fate in the environment are expected to be different. In this experiment, three chiral herbicides —bromacil, fenoxaprop, quizalofop, which we tested are sold and applied as racemic mixture. For bromacil, soil sample taken from a field plot at in- creasing time intervals after application of “hyvar”, a com- mercial herbicide formulation, were solvent extracted and analyzed by 2-dimention HPLC, using a C18 and a chirobiotic T column. In addition, hyvar were applied to three species of weeds. For fenoxaprop and quizalofop, the soil sample was also taken from a field plot at increasing time intervals after appli- cation of “stand racemic mixture” and analyzed the same as that of bromacil. The results indicate that the degradation of all species from weeds and soil sample are none enantioselective. However, further investigation is required for accurate their distributions and fate in the environment.

Herein is reported the synthesis of molecular probes for action of neuroactive steroids in vitro and in living organisms. In the first part, preparation of enantiomeric pregnane steroids is investigated, ultimately resulting into the total synthesis of ent-progesterone. The chirality of the target molecule is introduced by a highly effective organocatalytic asymmetric Robinson annulation. A new method for the sequential construction of five-membered carbocyclic ring is introduced as the key step. This is composed of substrate-controlled copper-catalyzed conjugate addition followed by radical oxygenation and subsequent thermal cyclization employing the persistent radical effect. The synthesis of truncated neurosteroid analogs is described and their biological activity at the NMDA receptor is compared with the native hormone. In the second part, methodology for specific deuterium labeling of both angular methyls of the 5β-pregnane steroid core is explored. Special attention was paid to the Barton-McCombie deoxygenation as the tool for introduction of the last deuterium atom into the methyl group. Both positions were labelled with total of three deuterium atoms in high isotopic purity.