Introduction and Objectives: The PDGFβ receptor and its ligand, PDGF-BB, are expressed throughout the central nervous system (CNS), including the hippocampas. Several reports confirm that PDGFβ receptors are neuroprotective against N-methyl-D-asparate (NMDA)-induced cell death in hippocampal neurons. NMDA receptor dysfunction is important for the expression of many symptoms of mental health disorders such as schizophrenia. The serotonin (5-HT) type 7 receptor was the most recent of the 5-HT receptor family to be identified and cloned. 5-HT receptors interact with several signaling systems in the CNS including receptors activated by the excitatory neurotransmitter glutamate such as the NMDA receptor. Although there is extensive interest in targeting the 5-HT7 receptor with novel therapeutic compounds, the function and signaling properties of 5-HT7 receptors in neurons remains poorly characterized. Methods: The SH-SY5Y neuroblastoma cell line, primary hippocampal cultures, and hippocampal slices were treated with 5-HT7 receptor agonists and antagonists. Western blotting was used to measure PDGFß receptor expression and phosphorylation as well as NMDA receptor subunit expression and phosphorylation levels. Real-time RT-PCR was used to measure mRNA level of PDGFß receptor in neuronal cultures. Cell death assays (MAP2, MTT) were used to measure the neuroprotective effects of 5-HT7 and PDGFß receptor activation. Results: My research involved elucidating the molecular mechanisms of neuroprotection after 5-HT7-induced PDGFß receptor upregulation. I demonstrated that 24 h treatment with the selective 5-HT7 receptor agonist, LP 12, increased not only the expression but also the activation of PDGFß receptors as measured by the phosphorylation of tyrosine 1021, the phospholipase Cγ binding site. Activation of the 5-HT7 receptor also selectively changed the expression and phosphorylation state of the NR2B subunit of the NMDA receptor. Activation of 5-HT7 receptors was neuroprotective against NMDA-induced toxicity in primary hippocampal neurons and this effect required PDGFß receptor kinase activity. Thus, long-term (24 h) activation of 5-HT7 receptors was neuroprotective via increasing the expression of a negative regulator of NMDA activity, the PDGFß receptor. In contrast, acute activation (5-30 min) of 5-HT7 receptor increased NMDA evoked current and altered NMDA receptor subunit phosphorylation in hippocampal neurons in a manner that was different from what we observed in our 24 h experiments. Conclusions: I identified two 5-HT7 receptor to NMDA receptor pathways: acute activation of the receptor increased NMDA-evoked currents whereas long-term 5-HT7 agonist treatment prevented NMDA-induced excitotoxicity in a PDGFß receptor-dependent manner. This research is significant in the ongoing advances for the treatment of mental heath disorders, such as schizophrenia and depression, that involve the 5-HT, glutamate, and neuronal growth factor systems.

The 5-HT7 receptor is the most recent addition to the 5-HT receptor family and has been linked to a variety of physiological and pathophysiological processes. Well established antide-pressant pharmaceuticals have recently been found to activate the 5-HT7 receptor, supporting the role of the 5-HT7 receptor in the antidepressant mechanism. The synthesis of potent selec-tive 5-HT7 receptor antagonists could afford a greater understanding of the 5-HT7 receptor function as well as lead to potential drug candidates. The synthesis of unfused biheteroaryl derivatives as 5-HT7 receptor ligands has been de-scribed within. These compounds have been tested for biological activity on the 5-HT6 and 5-HT7 receptors. 4-(3’-Furyl)-2-(N-substituted-piperazino)pyrimidines were found to be potent 5-HT7 receptor ligands. 4-(2’-Furyl)-2-(N-substituted-piperazino)pyrimidines have shown high se-lectivity for the 5-HT7 receptor over the 5-HT6 receptor.

The 5-HT7 receptor is the most recent addition to the 5-HT receptor family and has been linked to a variety of physiological and pathophysiological processes. Well established antide-pressant pharmaceuticals have recently been found to activate the 5-HT7 receptor, supporting the role of the 5-HT7 receptor in the antidepressant mechanism. The synthesis of potent selec-tive 5-HT7 receptor antagonists could afford a greater understanding of the 5-HT7 receptor function as well as lead to potential drug candidates. The synthesis of unfused biheteroaryl derivatives as 5-HT7 receptor ligands has been de-scribed within. These compounds have been tested for biological activity on the 5-HT6 and 5-HT7 receptors. 4-(3’-Furyl)-2-(N-substituted-piperazino)pyrimidines were found to be potent 5-HT7 receptor ligands. 4-(2’-Furyl)-2-(N-substituted-piperazino)pyrimidines have shown high se-lectivity for the 5-HT7 receptor over the 5-HT6 receptor.

The development of novel selective 5-HT6 and 5-HT7 receptor antagonists is an ever-growing area of interest among medicinal chemists. The potential of developing a therapeutic agent useful as an antipsychotic or antidepressant, as well as the possibility to develop a drug for Alzheimer’s disease and obesity has led to an increase in synthesis of possible lead compounds. The synthesis of unfused biheteroaryl derivatives is described within. The derivatives have been evaluated for binding affinity at 5-HT2A, 5-HT6 and 5-HT7 receptors. The most potent 5-HT6 receptor antagonists include a benzene ring, a hydrophobic group and a protonated nitrogen atom. The most potent and selective compound synthesized is 1-[3-butyl-5-(thienyl)phenyl]-4-methylpiperazine. The binding site of the 5-HT7 receptor is similar to that of the 5-HT6 receptor and the most selective and potent 5-HT7 receptor antagonist also contains a potonated nitrogen atom and a hydrophobic group. The difference in selectivity between the 5-HT6 and 5-HT7 receptor antagonists is the aromatic ring. The most potent 5-HT7 receptor antagonist synthesized contains a pyridine ring instead of benzene, as in the 5-HT6 receptor antagonist. The most potent and selective 5-HT7 receptor antagonist is 1-[4-(3-furyl)-6-methylpyridin-2-yl]-4-methylpiperazine. The need to increase selectivity for both 5-HT6 and 5-HT7 receptors has led to the synthesis of flexible-chain linked derivatives and the results are described within.

The development of novel selective 5-HT6 and 5-HT7 receptor antagonists is an ever-growing area of interest among medicinal chemists. The potential of developing a therapeutic agent useful as an antipsychotic or antidepressant, as well as the possibility to develop a drug for Alzheimer’s disease and obesity has led to an increase in synthesis of possible lead compounds. The synthesis of unfused biheteroaryl derivatives is described within. The derivatives have been evaluated for binding affinity at 5-HT2A, 5-HT6 and 5-HT7 receptors. The most potent 5-HT6 receptor antagonists include a benzene ring, a hydrophobic group and a protonated nitrogen atom. The most potent and selective compound synthesized is 1-[3-butyl-5-(thienyl)phenyl]-4-methylpiperazine. The binding site of the 5-HT7 receptor is similar to that of the 5-HT6 receptor and the most selective and potent 5-HT7 receptor antagonist also contains a potonated nitrogen atom and a hydrophobic group. The difference in selectivity between the 5-HT6 and 5-HT7 receptor antagonists is the aromatic ring. The most potent 5-HT7 receptor antagonist synthesized contains a pyridine ring instead of benzene, as in the 5-HT6 receptor antagonist. The most potent and selective 5-HT7 receptor antagonist is 1-[4-(3-furyl)-6-methylpyridin-2-yl]-4-methylpiperazine. The need to increase selectivity for both 5-HT6 and 5-HT7 receptors has led to the synthesis of flexible-chain linked derivatives and the results are described within.

No description available.

Of the seven existing classes of serotonin receptors, the 5-HT7 receptors (5-HT7Rs) are the most recently discovered. Abundance of 5-HT7 in the central nervous system is suggestive of the receptor’s role in several physiological and pathophysiological functions. Existing research has afforded a number of compounds exhibiting specific affinity to the receptor. These selective ligands can provide structural information about the receptor and can serve as the foundation for pharmacological profiling . This thesis describes the synthesis of substituted pyrimidines and pyridines for affinity to the 5-HT7 receptor. Organometallic species are the cornerstone for sev-eral of the synthetic pathways.

The synthesis of a series of 2-chloropyrimidine derivatives is described. The synthesis began with a nucleophilic addition of lithiated heterocyclic molecules to the 4 position of 2-chloropyrimidine to give dihydropyrimidine intermediates. The intermediates were oxidized to the pyrimidine ring using the DDQ method. This was followed by an addition-elimination reaction of an amine to the 2-chloropyrimidine derivative. The structure and properties of the final compounds were analyzed by melting point, combustion analysis, and 13C-NMR and 1H-NMR spectroscopy. Biological activities in vitro of the synthesized compounds as antagonists of the 5-HT2a and 5-HT7 receptors were determined by an independent laboratory.

Novel and potent ligands to the serotonin7 (5-HT7) receptor have been synthesized. The synthesized compounds include a set of substituted pyrimidines which show high affinity to the 5-HT7 receptor, synthesized by previously described methods [1,2] in high yield. Comparing the affinities of substituted pyrimidines to previously calculated models [3,4] yielded new hypotheses about the nature of interaction between the pyrimidine ligands and the 5-HT7 binding site. Several new series of compounds were synthesized by various methods to validate these hypotheses, including a conjugate addition to vinylpyrimidines [5]. These compounds include benzofurans, oximes, hydrazones, as well as a group of substituted piperazines. All series of compounds show affinity to the 5-HT7 receptor comparable to previously synthesized 5-HT7 ligands. Several of the synthesized ligands show affinity which exceeds that of currently available ligands. The synthesized compounds were evaluated quantitatively by calculating a three-dimensional quantitative structure-affinity relationship (3D-QSAR) for the 5-HT7 receptor. Evaluation of the calculated model validated qualitative assumptions about the data set as well as described regions of interaction in greater detail than previously available. These observations give further insight on the nature of ligand-binding site interactions with highly potent ligands such as 4-(3-furyl)-2-(N-methylpiperazino)pyrimidine which will lead to more potent 5-HT7 receptor ligands. Additionally, a model was calculated for affinity to the 5-HT2a receptor. Comparing this model to that calculated for affinity to the 5-HT7 receptor identified two regions which may be exploited in future sets of ligands to increase selectivity to the 5HT7 receptor.

In this thesis, rodent models of chronic pain were used to explore analgesic mechanisms that may potentially be engaged in spinal and peripheral compartments by systemically-administered amitriptyline, a tricyclic antidepressant. The first project (Chapter 2) identified the roles of spinal adenosine A1 and serotonin 5-HT7 receptors, as well as of peripheral adenosine A1 receptors, in the acute antinociceptive effects of amitriptyline in mice. The second project (Chapter 3) examined the potential utility of amitriptyline as a preventive analgesic against persistent post-surgical pain, and involved perioperative administration of amitriptyline after peripheral nerve injury in rats. Changes in post-injury behavioural outcomes, as well as spinal noradrenergic sprouting, were assessed. Overall, spinal serotonergic pathways linked to adenosine A1 receptors, as well as peripheral adenosine A1 receptors, appear to be important in antinociception by amitriptyline. Preventive analgesia by this drug does not appear to result from anatomical changes in spinal noradrenergic pathways.