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dc.contributor.advisorCanney, Daniel J.
dc.creatorBhandare, Richie R.
dc.date.accessioned2020-10-19T15:47:42Z
dc.date.available2020-10-19T15:47:42Z
dc.date.issued2013
dc.identifier.other864885981
dc.identifier.urihttp://hdl.handle.net/20.500.12613/580
dc.descriptionAccompanied by one .pdf file.
dc.description.abstractThe acetylcholine (ACh) receptor system belongs to rhodopsin GPCR family and is an integral membrane protein divided into two types: muscarinic and nicotinic. The naturally occurring neurotransmitter acetylcholine binds to these two receptor systems non- selectively. The regulatory effects of the neurotransmitter acetylcholine are diverse ranging from autonomic nervous system and the central nervous system through different types of neurons innervated by cholinergic inputs. Muscarinic acetylcholine receptors (mAChRs) are divided into five receptor subtypes (M1-M5). In general, M1, M3 and M5 receptor subtypes are coupled via Gq like proteins; while M2 and M4 subtypes are coupled to Gi-proteins. Muscarinic receptors are widely distributed in the body where they mediate a variety of important physiological effects. mAChRs have been the target of drug development efforts for the treatment of various disorders including overactive bladder, Alzheimer's disease, pain, cognitive impairment, drug addiction, schizophrenia and Parkinson's disease. The development subtype selective ligands possess a challenge due to a high degree of homology among mAChR subtypes, however the recent availability of the X-ray crystal structure for the M2 and M3 receptor can be utilized for the design of new ligands. The pharmacophoric requirements for cholinergic ligands have been reported by numerous investigators based on structure-activity relationship (SAR) and/or molecular modeling data of known muscarinic ligands. These fundamental requirements are useful when designing muscarinic ligands but have provided little guidance in the design of subtype selective compounds. Our interest in developing novel muscarinic receptor ligands led to the design of lactone-based ligands using an approach similar to that reported by Kaiser et al. Preliminary binding studies of our previously synthesized lactone based compounds indicated that several were nonselective, low affinity (IC50 = µM range) muscarinic agonists (based on preliminary in vivo data). Hence based on the background information, we decided to utilize the previously synthesized lactone parent compound as lead molecule set out to investigate a new series of lactone based compounds in order improve the affinity and later the selectivity of ligands. Bioisosteric approach has been investigated for the metabolic lability of the lactone ring. Four probable bioisosteres have been evaluated: tetrahydrofuran, 1,3-benzodioxole, oxazolidinone and chromone. Thermal/microwave assisted synthesis has been utilized in the generation of intermediates as well as final compounds. Preliminary screening and further evaluation (IC50/ subtype selectivity) has resulted in the identification of promising fragments as bioisosteres for the lactone ring.
dc.format.extent158 pages
dc.language.isoeng
dc.publisherTemple University. Libraries
dc.relation.ispartofTheses and Dissertations
dc.rightsIN 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.
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/
dc.subjectPharmaceutical Sciences
dc.subject1,3-benzodioxole
dc.subjectChromone
dc.subjectLactones
dc.subjectMuscarinic Receptors
dc.subjectOxazolidinone
dc.subjectTetrahydrofuran
dc.titleInvestigation into the bioisosteric approach in the design, synthesis and evaluation of muscarinic receptor ligands
dc.typeText
dc.type.genreThesis/Dissertation
dc.contributor.committeememberBorenstein, Michael R.
dc.contributor.committeememberAbou-Gharbia, Magid
dc.contributor.committeememberIlies, Marc A.
dc.contributor.committeememberHarrison, Boyd L.
dc.description.departmentPharmaceutical Sciences
dc.relation.doihttp://dx.doi.org/10.34944/dspace/562
dc.ada.noteFor Americans with Disabilities Act (ADA) accommodation, including help with reading this content, please contact scholarshare@temple.edu
dc.description.degreePh.D.
refterms.dateFOA2020-10-19T15:47:42Z


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