Design, synthesis and biological evaluation of novel multi-receptor ligands with potential application in schizophrenia therapeutics

Strathclyde theses - ask staff. Thesis no. : T13187Schizophrenia is a debilitating disease that affects approximately 1 % of the population worldwide. 5-HT7 antagonist, M4 agonist and low D2 antagonist 53 was shown to alleviate schizophrenia-like symptoms in vivo. However, this compound was later found to possess significant hERG liability (Figure 1). Figure 1: Proof of concept lead serominic amidine compound 53 at physiological pH. The human ether-à-go-go related gene (hERG) codes for a specific potassium ion channel in the heart and blockade of this channel by drugs can cause sudden death. The research programme focused mainly on reduction of hERG activity via pKa modulation by introduction of a linker with an electron-withdrawing group (EWG) in place of the basic (pKa = 12) amidine linker (Figure 2). Figure 2: pKa attenuation upon insertion of EWG. A number of analogous compounds with EWG linkers were synthesised and all compounds successfully reduced hERG activity compared to the lead amidine (53) (Figure 3). Figure 3: Schematic depicting hERG liability of each linker group compared to the amidine linker. The incorporation of an EWG linker has been discovered as a valuable strategy in reduction of hERG liability. Furthermore, a number of novel pathfinder compounds with promising multi-receptor profiles have been designed, synthesised and evaluated in radioligand binding assays. Further work may provide evidence for the utility of these multi-ligands as a new generation of antipsychotic therapies.Schizophrenia is a debilitating disease that affects approximately 1 % of the population worldwide. 5-HT7 antagonist, M4 agonist and low D2 antagonist 53 was shown to alleviate schizophrenia-like symptoms in vivo. However, this compound was later found to possess significant hERG liability (Figure 1). Figure 1: Proof of concept lead serominic amidine compound 53 at physiological pH. The human ether-à-go-go related gene (hERG) codes for a specific potassium ion channel in the heart and blockade of this channel by drugs can cause sudden death. The research programme focused mainly on reduction of hERG activity via pKa modulation by introduction of a linker with an electron-withdrawing group (EWG) in place of the basic (pKa = 12) amidine linker (Figure 2). Figure 2: pKa attenuation upon insertion of EWG. A number of analogous compounds with EWG linkers were synthesised and all compounds successfully reduced hERG activity compared to the lead amidine (53) (Figure 3). Figure 3: Schematic depicting hERG liability of each linker group compared to the amidine linker. The incorporation of an EWG linker has been discovered as a valuable strategy in reduction of hERG liability. Furthermore, a number of novel pathfinder compounds with promising multi-receptor profiles have been designed, synthesised and evaluated in radioligand binding assays. Further work may provide evidence for the utility of these multi-ligands as a new generation of antipsychotic therapies

Replacement of dichloromethane within chromatographic purification : a guide to alternative solvents

Replacement of dichloromethane as the bulk medium within chromatographic purification has been evaluated with a broad range of molecules containing functionality common within Medicinal Chemistry programmes. Analysis of the data set has generated a set of general guidelines to assist in the selection of alternative solvents for CH2Cl2 as the bulk media in these ubiquitously employed processes

Design, synthesis and antibacterial activity of minor groove binders: the role of non-cationic tail groups

he design and synthesis of a new class of minor groove binder (MGBs) in which, the cationic tail group has been replaced by a neutral, polar variant including cyanoguanidine, nitroalkene, and trifluoroacetamide groups. Antibacterial activity (against Gram positive bacteria) was found for both the nitroalkene and trifluoroacetamide groups. For the case of the nitroalkene tail group, strong binding of a minor groove binder containing this tail group was demonstrated by both DNA footprinting and melting temperature measurements, showing a correlation between DNA binding and antibacterial activity. The compounds have also been evaluated for binding to the hERG ion channel to determine whether non-cationic but polar substituents might have an advantage compared with conventional cationic tail groups in avoiding hERG binding. In this series of compounds, it was found that whilst non-cationic compounds generally had lower affinity to the hERG ion channel, all of the compounds studied bound weakly to the hERG ion channel, probably associated with the hydrophobic head groups

Priorities for research in child maltreatment, intimate partner violence and resilience to violence exposures: results of an international Delphi consensus development process

Background Intimate partner violence (IPV) and child maltreatment (CM) are major global public health problems. The Preventing Violence Across the Lifespan (PreVAiL) Research Network, an international group of over 60 researchers and national and international knowledge-user partners in CM and IPV, sought to identify evidence-based research priorities in IPV and CM, with a focus on resilience, using a modified Delphi consensus development process. Methods Review of existing empirical evidence, PreVAiL documents and team discussion identified a starting list of 20 priorities in the following categories: resilience to violence exposure (RES), CM, and IPV, as well as priorities that cross-cut the content areas (CC), and others specific to research methodologies (RM) in violence research. PreVAiL members (N = 47) completed two online survey rounds, and one round of discussions via three teleconference calls to rate, rank and refine research priorities. Results Research priorities were: to examine key elements of promising or successful programmes in RES/CM/IPV to build intervention pilot work; CC: to integrate violence questions into national and international surveys, and RM: to investigate methods for collecting and collating datasets to link data and to conduct pooled, meta and sub-group analyses to identify promising interventions for particular groups. Conclusions These evidence-based research priorities, developed by an international team of violence, gender and mental health researchers and knowledge-user partners, are of relevance for prevention and resilience-oriented research in the areas of IPV and CM

Priorities for research in child maltreatment, intimate partner violence and resilience to violence exposures:results of an international Delphi consensus development process

BACKGROUND: Intimate partner violence (IPV) and child maltreatment (CM) are major global public health problems. The Preventing Violence Across the Lifespan (PreVAiL) Research Network, an international group of over 60 researchers and national and international knowledge-user partners in CM and IPV, sought to identify evidence-based research priorities in IPV and CM, with a focus on resilience, using a modified Delphi consensus development process. METHODS: Review of existing empirical evidence, PreVAiL documents and team discussion identified a starting list of 20 priorities in the following categories: resilience to violence exposure (RES), CM, and IPV, as well as priorities that cross-cut the content areas (CC), and others specific to research methodologies (RM) in violence research. PreVAiL members (N = 47) completed two online survey rounds, and one round of discussions via three teleconference calls to rate, rank and refine research priorities. RESULTS: Research priorities were: to examine key elements of promising or successful programmes in RES/CM/IPV to build intervention pilot work; CC: to integrate violence questions into national and international surveys, and RM: to investigate methods for collecting and collating datasets to link data and to conduct pooled, meta and sub-group analyses to identify promising interventions for particular groups. CONCLUSIONS: These evidence-based research priorities, developed by an international team of violence, gender and mental health researchers and knowledge-user partners, are of relevance for prevention and resilience-oriented research in the areas of IPV and CM

Evaluation of alternative solvents in common amide coupling reactions : replacement of dichloromethane and N,N-dimethylformamide

A range of alternative solvents have been evaluated within amidation reactions employing common coupling reagents with a view to identifying suitable replacements for dichloromethane and N,N-dimethylformamid

Selective anti-Leishmanial Strathclyde minor groove binders using an N-oxide tail group modification

The neglected tropical disease leishmaniasis, caused by Leishmania spp., is becoming more problematic due to the emergence of drug-resistant strains. Therefore, new drugs to treat leishmaniasis, with novel mechanisms of action, are urgently required. Strathclyde minor groove binders (S-MGBs) are an emerging class of anti-infective agent that have been shown to have potent activity against various bacteria, viruses, fungi and parasites. Herein, it is shown that S-MGBs have potent activity against L. donovani, and that an N-oxide derivation of the tertiary amine tail of typical S-MGBs leads to selective anti-leishmanial activity. Additionally, using S-MGB-219, the N-oxide derivation is shown to retain strong binding to DNA as a 2:1 dimer. These findings support the further study of anti-leishmanial S-MGBs as novel therapeutics

Beliefs About Medication and Uptake of Preventive Therapy in Women at Increased Risk of Breast Cancer: Results From a Multicenter Prospective Study

Introduction Uptake of preventive therapies for breast cancer is low. We examined whether women at increased risk of breast cancer can be categorized into groups with similar medication beliefs, and whether belief group membership was prospectively associated with uptake of preventive therapy. Patients and Methods Women (n = 732) attending an appointment to discuss breast cancer risk were approached; 408 (55.7%) completed the Beliefs About Medicines and the Perceived Sensitivity to Medicines questionnaires. Uptake of tamoxifen at 3 months was reported in 258 (63.2%). The optimal number of belief groups were identified using latent profile analysis. Results Uptake of tamoxifen was 14.7% (38/258). One in 5 women (19.4%; 78/402) reported a strong need for tamoxifen. The model fit statistics supported a 2-group model. Both groups held weak beliefs about their need for tamoxifen for current and future health. Group 2 (38%; 154/406 of the sample) reported stronger concerns about tamoxifen and medicines in general, and stronger perceived sensitivity to the negative effects of medicines compared with group 1 (62%; 252/406). Women with low necessity and lower concerns (group 1) were more likely to initiate tamoxifen (18.3%; 33/180) than those with low necessity and higher concerns (group 2) (6.4%; 5/78). After adjusting for demographic and clinical factors, the odds ratio was 3.37 (95% confidence interval, 1.08-10.51; P = .036). Conclusion Uptake of breast cancer preventive therapy was low. A subgroup of women reported low need for preventive therapy and strong medication concerns. These women were less likely to initiate tamoxifen. Medication beliefs are targets for supporting informed decision-making

Spatial limits of visuotactile interactions in the presence and absence of tactile stimulation

The presence of a light flash near to the body not only increases the ability to detect a weak touch but also increases reports of feeling a weak touch that did not occur. The somatic signal detection task (SSDT) provides a behavioural marker by which to clarify the spatial extent of such visuotactile interactions in peripersonal space. Whilst previous evidence suggests a limit to the spatial extent over which visual input can distort the perception of tactile stimulation during the rubber hand illusion, the spatial boundaries of light-induced tactile sensations are not known. In a repeated measures design, 41 participants completed the SSDT with the light positioned 1 cm (near), 17.5 cm (mid) or 40 cm (far) from the tactile stimulation. In the far condition, the light did not affect hit, or false alarm rates during the SSDT. In the near and mid conditions, the light significantly increased hit rates and led to a more liberal response criterion, that is, participants reported feeling the touch more often regardless of whether or not it actually occurred. Our results demonstrate a spatial boundary over which visual input influences veridical and non-veridical touch perception during the SSDT, and provide further behavioural evidence to show that the boundaries of the receptive fields of visuotactile neurons may be limited to reach space