The synthesis and pharmacological evaluation of quisqualic acid and some novel excitatory amino acid mimetics

L-Glutamic acid and L-aspartic acid are believed to be the principal initiators of excitatory synaptic neurotransmission in the mammalian central system. A number of molecules of either natural or synthetic origin have been identified as possessing agonist or antagonist properties at glutamate binding sites. One of the most potent agonist is quisqualic acid (69), and this thesis features two aspects of the synthetic organic chemistry and the pharmacology of quisqualic acid and some of its analogues

Modeling complex metabolic reactions, ecological systems, and financial and legal networks with MIANN models based on Markov-Wiener node descriptors

[Abstract] The use of numerical parameters in Complex Network analysis is expanding to new fields of application. At a molecular level, we can use them to describe the molecular structure of chemical entities, protein interactions, or metabolic networks. However, the applications are not restricted to the world of molecules and can be extended to the study of macroscopic nonliving systems, organisms, or even legal or social networks. On the other hand, the development of the field of Artificial Intelligence has led to the formulation of computational algorithms whose design is based on the structure and functioning of networks of biological neurons. These algorithms, called Artificial Neural Networks (ANNs), can be useful for the study of complex networks, since the numerical parameters that encode information of the network (for example centralities/node descriptors) can be used as inputs for the ANNs. The Wiener index (W) is a graph invariant widely used in chemoinformatics to quantify the molecular structure of drugs and to study complex networks. In this work, we explore for the first time the possibility of using Markov chains to calculate analogues of node distance numbers/W to describe complex networks from the point of view of their nodes. These parameters are called Markov-Wiener node descriptors of order kth (Wk). Please, note that these descriptors are not related to Markov-Wiener stochastic processes. Here, we calculated the Wk(i) values for a very high number of nodes (>100,000) in more than 100 different complex networks using the software MI-NODES. These networks were grouped according to the field of application. Molecular networks include the Metabolic Reaction Networks (MRNs) of 40 different organisms. In addition, we analyzed other biological and legal and social networks. These include the Interaction Web Database Biological Networks (IWDBNs), with 75 food webs or ecological systems and the Spanish Financial Law Network (SFLN). The calculated Wk(i) values were used as inputs for different ANNs in order to discriminate correct node connectivity patterns from incorrect random patterns. The MIANN models obtained present good values of Sensitivity/Specificity (%): MRNs (78/78), IWDBNs (90/88), and SFLN (86/84). These preliminary results are very promising from the point of view of a first exploratory study and suggest that the use of these models could be extended to the high-throughput re-evaluation of connectivity in known complex networks (collation)

The role of phenytoin (5, 5-diphenylhydantoin) and structurally related compounds in wound healing.

Low concentrations of PHT (5-10g/ml) were found to upregulate the proliferation of some fibroblast and keratinocyte cell lines, but not others. Micro Chemotaxis Chamber assays revealed PHG (5-50g/ml) to be a chemoattractant for both normal and RDEB fibroblasts and keratinocytes, indicating that it may facilitate the recruitment of cells into the wound space. Prolonged treatment with PHG (20g/ml) reduced the contraction of both the normal and the hypercontractile RDEB fibroblasts in vitro as measured by the reduction in surface area of untethered fibroblast-populated collagen lattices or directly by the Culture Force Monitor. Good correlations were observed with this finding in vivo in reducing wound contraction of pigs without impairment of healing after two or three weeks post-operatively (with either PHT powder or incorporated into Fibrin Sealant). The effects of compounds structurally related to PHT were also investigated to see if a structure-activity relationship could be determined which would provide clues for the design of new drugs for wound healing. Both Micro Chemotaxis Chamber assays and Culture Force Monitor measurements indicated that metabolites of PHT were more active than the parent compound

Drug Management of Epilepsy: Current Problems and the Possible Role of Calcium Antagonists

Prologue and Introduction Epilepsy is a disease which has struck fear into the hearts of both sufferers and onlookers for many centuries. Only in the past hundred years or so has effective medication become available, and medical management still relies on a small group of antiepileptic drugs (AEDs). These can often abolish seizures, and very frequently diminish their frequency such that patients can enjoy a normal life-style. A significant minority of patients, however, do not respond satisfactorily. Combining different drugs is complicated by their sharing the same side-effect - sedation - which seems more additive than does any therapeutic effect. It is for the benefit of these patients with refractory epilepsy that research continues, to improve our use of the present AEDs, and to find new drugs which might, when used alone or in combination, improve their lot. Therapeutic Drug Monitoring (TDM) In Chapter 1, current use of TDM in the epilepsy clinic is analysed. By recording physicians' decisions both before and after serum anticonvulsant concentrations were made available at 488 clinic visits, we found that management decisions were affected at 23% of these consultations. However, physicians did not appear to follow a "target concentration strategy" as a high proportion of results (26%) in the "target range" were followed by a change in dosage. A drawback with the "target concentration strategy" was highlighted by the correlation between carbamazepine concentration and time since dosing (P< 0.005). The possible benefits of an approach combining clinical and biochemical information are discussed. Cognitive function In Chapter 2, the effects of many AEDs on mental function are assessed. Deterioration in "cognitive" or "psychomotor" abilities is a generally recognised side-effect of all current AEDs. However, most evidence compares patients taking AEDs with healthy volunteers, the effect on mental function of the disease itself thus being uncontrolled. Other studies show short term deterioration in volunteers given AEDs for a limited period, or in patients abruptly taking an increased dose. These respectively fail to allow for any beneficial effect which controlling seizures might have on mental function, and the effect of tolerance to the drugs' side-effects. In EXPT. 2, 66 patients on AED therapy performed a battery of psychomotor function tests, and their results were compared with those of 14 untreated epileptic patients and 11 healthy controls. A clear "step-wise" deterioration in function was seen with reaction times, short-term memory, card-sorting, and finger-tapping speeds. Untreated epileptics fared worse than controls (P <0.05 - P <0.001) but better than treated patients (P< 0.05 -P <0.01). This demonstrated the deliterious effect of epilepsy itself. The drugs may aggravate this, though clearly the treated patients had more severe epilepsy. No differences were found between the individual drugs. In EXPT. 3, the effect of tolerance was demonstrated in a small group (n=13) of new patients commenced on carbamazepine. After an initial deterioration in reaction time (P<0.05) and finger-tapping (P< 0.001) at one week, these abilities returned to normal by twelve weeks, while mean serum concentrations of carbamazepine only fell from 8.5 mg/L to 7.1 mg/L. The relevance of short-term cognitive deterioration demonstrated in many studies is thus brought into question. Since diurnal variation in serum concentrations has been shown to correlate with carbamazepine neurotoxicity, EXPT. 4 tested the pharmacokinetics of a controlled-release preparation (Tegretol Retard, CBZ-CR). Eight healthy volunteers took this and conventional carbamazepine 200mg bd for two weeks in a double-blind, crossover fashion. Serum concentrations "plateaued" for 56h after single dose CBZ-CR, while chronic dosing resulted in diurnal fluctuation of only 12% compared with 24% on conventional carbamazepine (P <0.025), and produced less rapid changes in concentration (P< 0.02). Enzyme induction appeared similar with both preparations, but the bioavailability of CBZ-CR was possibly slightly lower. The "smoother" pharmacokinetic profile of CBZ-CR did not produce a detectable improvement in psychomotor function. Enzyme induction Many AEDs (carbamazepine, phenytoin, phenobarbitone) induce an increase in hepatic metabolising enzyme activity. This results in accelerated metabolism of the drugs themselves, of some other drugs which undergo oxidative metabolism, and of endogenous hormones. The clinical implications of this last aspect remain unclear. (Abstract shortened by ProQuest.)

Design and synthesis of novel ligands for Serotonin (5-HT6) receptor and inhibitors of ABCB1 Efflux pump

Selenium and Biology have a unique relationship. Selenium is an element which exists in several amino acids, including selenocysteine and selenomethionine. It plays several vital roles in the human body and is essential for several physiological processes. The last few years have witnessed the development of a new generation of biologically active and pharmaceutically relevant organo-selenium compounds, ranging from effective anticancer agents to novel ligands for serotonin 5-HT6 receptors and ABCB1 efflux pump modulators. This study describes the role of phenylselenoether-hydantoin hybrids as ABCB1 efflux pump modulating agents. Moreover, this work aims to synthesize novel and highly (re)active agents employing triazine-methyl piperazine hybrids for therapeutic applications in the treatment of current civilization central nervous system disorder. In summary, a library of 50 active novel compounds has been prepared to serve as efflux pump modulators or 5-HT6 ligands. Melting point, mass spectroscopy (MS), and nuclear magnetic resonance spectroscopy (NMR) evaluation have been employed to establish and confirm the structure of the compounds. The biological assays have been performed to evaluate their affinity towards 5HT6 receptor or efflux pump modulating ability. Finally, structure-activity relationship analysis has been performed to review and suggest modifications for the pharmacophore features.Selen ist ein Element, das in mehreren Aminosäuren, einschließlich Selenocystein und Selenomethionin, vorkommt. Es spielt verschiedene lebenswichtige Rollen im menschlichen Körper und ist für zahlreiche physiologische Prozesse unerlässlich. In den letzten Jahren wurde eine neue Generation biologisch aktiver und pharmazeutisch relevanter Organo-Selen-Verbindungen entwickelt, die von wirksamen Krebsbekämpfungsmitteln bis hin zu neuartigen Liganden für Serotonin-5-HT6-Rezeptoren und ABCB1-Effluxpumpenmodulatoren reichen. Diese Studie beschreibt die Rolle von Phenylselenoether-Hydantoin-Hybriden als ABCB1- Effluxpumpenmodulatoren sowie die Synthese von neuartigen und hoch (re)aktiven Wirkstoffen unter Verwendung von Triazin-Methylpiperazin-Hybriden für therapeutische Anwendungen bei der Behandlung von Störungen des Zentralnervensystems der modernen Gesellschaft Zivilisation. Zusammenfassend lässt sich sagen, dass eine Bibliothek von 50 aktiven neuartigen Verbindungen vorbereitet wurde, die als Effluxpumpenmodulatoren oder 5-HT6-Liganden dienen sollen. Die Verbindungen wurden durch Schmelzpunkt-, Massenspektroskopie- (MS) und Kernresonanzspektroskopie- (NMR) charakterisiert. Biologische Assays wurden durchgeführt, um die Fähigkeit der synthetisierten Verbindungen zur Modulierung des 5HT6-Rezeptors oder der Effluxpumpe zu bestimmen. Schließlich wurde eine Struktur-Aktivitäts Beziehungsanalyse durchgeführt, um die pharmakophoren Eigenschaften zu überprüfen und Änderungen vorzuschlagen

The mechanism of racemisation of 5-substituted hydantoins in aqueous solution

This thesis describes our studies of the racemisation of substituted hydantoins and is divided in six chapters. Chapter 1 presents the concepts of chirality and racemisation and its implications in drug development. The literature on the stereolability of 5-substituted hydantoins is summarised. Chapter 2 describes detailed kinetic and mechanistic studies of the racemisation of (5)-5-benzylhydantoin and (5)-3-iV-methyl-5-benzylhydantoin, aimed at establishing the mechanistic aspects of racemisation of these molecules. Kinetics of H/D exchange and racemisation, kinetic isotope effects, and solvent kinetic isotope effects all favour the SeI mechanism of racemisation as opposed to the Se2 process proposed by others. Chapter 3 discusses the effects of structural modifications on the stereolability of a series of model 5-substituted hydantoins with improved water solubility as compared to (iS)-5-benzylhydantoin and (5)-3-A-methyl-5-benzylhydantoin. Hydantoins containing a protonated amino or an ammonium group showed increased stereolability. This finding was attributed to intramolecular facilitation of racemisation by the positive charge. The primary and solvent kinetic isotope effects on the racemisation of two model 5-substituted hydantoins were determined and again supported an SeI mechanism of racemisation. Chapter 4 deals with solvent effects on racemisation and H/D exchange of a series of 5-benzylhydantoins. DMSO added to phosphate buffers showed a marked rate-increasing effect for all of the substrates under study. Co-added 2-propanol and dioxane showed a rate-decreasing effect on neutral hydantoins and a rate-increasing effect on a cationic hydantoin. Solvent effects on the basicity of anionic catalysts and phenomena of preferential solvation were proposed as important factors affecting the rate constants in mixed media. Chapter 5 reports the preliminary results of exploratory experiments aimed at assessing potentials and limitations of VCD and IR spectroscopy for kinetic and mechanistic studies of racemisation. Finally, Chapter 6 summarises our findings and presents recommendation for future work

Synthesis and pharmacological evaluation of primary amino acid derivatives (PAADs): novel neurological agents for the treatment of epilepsy and neuropathic pain

Epilepsy and neuropathic pain (NP) are chronic neurological disorders that result from dysregulations in neuronal function. Currently, there is a lack of adequate therapeutic agents available to treat these disorders and the need remains to develop compounds that possess a novel mechanism of action to address the shortcomings of current medications. Recently, the role of voltage-gated sodium channels (VGSCs) has been implicated in the pathophysiological mechanisms of NP, while their role in epilepsy has been known for some time. The functionalized amino acid (FAA) (R)-lacosamide is an emerging antiepileptic drug (AED) that has been shown to selectively promote VGSCs into the slow inactivated state and has recently been approved by the EMEA and the US FDA under the trademark Vimpat[registered trademark] for the adjuvant treatment of partial-onset seizures in adults. (R)-Lacosamide has also demonstrated clinical efficacy in treating painful diabetic neuropathy, but has yet to gain regulatory approval for this indication. The pharmaceutical industry has made advances in developing peripheral nervous system (PNS)-specific agents that target specific isoforms of VGSCs for the treatment of NP. We combined the concept of PNS-selectivity with our knowledge of FAAs and proposed that primary amino acid derivatives (PAADs) may selectively target PNS receptor sites, thereby avoiding potential CNS side effects that makes adherence to pain therapy difficult. Additionally, we examined the effect of PAADs on CNS function due to the excellent anticonvulsant activity of FAAs. We synthesized and evaluated over 50 PAADs in whole animal models of epilepsy and NP, and developed a structure-activity relationship (SAR) that defined the structural requirements for PAAD activity. The SAR revealed excellent anticonvulsant activity and pain attenuation for a novel class of compounds, the C(2)-hydrocarbon PAADs. Then, we synthesized over 40 additional PAADs to optimize anticonvulsant activity and pain attenuation. From our optimization studies, we discovered two PAADs that displayed superior anticonvulsant activity and may rival the therapeutic capabilities of (R)-lacosamide. Finally, we evaluated the most active PAADs in a series of binding and enzymatic assays but we did not reveal any new binding targets of therapeutic relevance