Muscarinic receptors are G-protein-coupled receptors that mediate the response to acetylcholine released from parasympathetic nerves. Although five mAChR subtypes (M1-M5) share a high degree of homology, they display different physiological effects including controlling smooth muscle tone to neurotransmitter release in the CNS. Hence these receptor subtypes have been investigated as potential therapeutic targets for agents capable of treating Alzheimer's Disease, Parkinson's Disease, peptic ulcer disease, COPD, urinary incontinence, and muscle spasms. Our interest in the development of subtype selective muscarinic ligands led to previous reports detailing the identification of substituted lactones as lead muscarinic compounds. Later work involved molecular modifications of those leads that included the addition of aromatic groups with a variety of substitution patterns. These efforts led to an increase in receptor affinity and produced a lactone-based muscarinic ligand with an IC50 of 340nM. As a continuation of that work, additional novel ligands were designed based on the general pharmacophoric elements proposed for the lactone-based ligands. In that model, the lactone oxygens serve as H-bond acceptor moieties while different nitrogen containing heterocycles provide the requisite cationic group. These groups may be separated by linker groups of varying sizes. In order to synthesize the lactone-based ligands mentioned above, efficient synthetic routes are required for key precursors. These include but are not limited to: 1. A novel high yield synthesis of the hydroxyethyl-lactone precursor was designed using a carefully controlled Prins reaction. The method readily quenches a cationic intermediate and simultaneously protects hydroxyl groups in a single step. A mechanism for the new route to the precursor is proposed and its use in the preparation of the target compounds is presented 2. Microwave-assisted synthesis of various sterically hindered N-aryl piperazines has been developed allowing quick access to structurally diverse muscarinic ligands These synthesis along with other newly developed routes enabled ready access to 59 novel muscarinic ligands. The ligands were tested in a general muscarinic binding assay. The result was analyzed and SAR study was performed to direct ligand design. As a result of this work, ligand affinity was improved by over 100 folds compare to the lead molecules. Several promising compounds were selected and selectivity tested. / Pharmaceutical Sciences
| Identifer | oai:union.ndltd.org:TEMPLE/oai:scholarshare.temple.edu:20.500.12613/1266 |
| Date | January 2013 |
| Creators | Gao, Rong |
| Contributors | Canney, Daniel J., Abou-Gharbia, Magid, Childers, Wayne E., Borenstein, Michael R., Harrison, Boyd L. |
| Publisher | Temple University. Libraries |
| Source Sets | Temple University |
| Language | English |
| Detected Language | English |
| Type | Thesis/Dissertation, Text |
| Format | 233 pages |
| Rights | IN COPYRIGHT- This Rights Statement can be used for an Item that is in copyright. Using this statement implies that the organization making this Item available has determined that the Item is in copyright and either is the rights-holder, has obtained permission from the rights-holder(s) to make their Work(s) available, or makes the Item available under an exception or limitation to copyright (including Fair Use) that entitles it to make the Item available., http://rightsstatements.org/vocab/InC/1.0/ |
| Relation | http://dx.doi.org/10.34944/dspace/1248, Theses and Dissertations |
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