DOCSLIB.ORG

Towards the Synthesis of Aromatic Analogues of Himbacine, Potential Muscarinic Ligands

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Towards the Synthesis of Aromatic Analogues of Himbacine, Potential Muscarinic Ligands TOWARDS THE SYNTHESIS OF AROMATIC ANALOGUES OF HIMBACINE, POTENTIAL MUSCARINIC LIGANDS A thesis submitted in fulfilment of the requirements for the degree of Doctor of Philosophy by Xue Qin Shi (B.E., M.Sc.) Supervisor: Associate Professor Roger W. Read SCHOOL OF CHEMISTRY THE UNIVERSITY OF NEW SOUTH WALES MAY2000 CERTIFICATE OF ORIGNALITY I hereby declare thatthis submission is my own workand that, to the best of my knowledge and belief, it contains no material previously published or written by another person nor material which to a substantial extent has been accepted for the award of any other degree or diploma of a university or other institute of higher learning, except where due acknowledgementis made in thetext . CERTIFICATEOF ORIGINALITY I hereby declare that this submission is my own worlc and to the best of my knowledge it contains no materials previously published or written by another person, nor material which to a substantial extent bas been accepted for the award of any other degree or diploma at UNSW or any other educational institution, except where due acknowledgement is made in the thesis. AJJ.y contnbution made to the research by others, with whom I have worlced at UNSW or elsewhere. is explicitly acknowledged in the thesis. I also declare that the intellectual content of this thesis is the product of my own work, except to the extent that assistance from others in the project's design and conception or in style, presentation and linguistic expression is acknowledged. 11 ACKNOLEDGEMENTS I am very grateful to my supervisor Associate Professor Roger W. Read for his guidance, enthusiasm, encouragement and patience throughout the course of this study. I also extend my thanks to my co-supervisor Prof. David StC. Black for his supervision while Roger was away on a Special Studies Program. I am thankful to all technical staff in the School of Chemistry, especially to Dr. Graha.111 Ball, Mrs. Hilda Stender and Dr. Jim Hook for their assistance in the 2-D n.m.r. experiments; to Dr. Joe Brophy and Mr. Rui Zhang for their useful help with the routine and high resolution mass spectra experiments. I would like to thank the members of the Read group for their friendship and enjoyable discussions on many subjects. It is also grateful to Dr. Neil Donoghue for his kindly proof reading part of this thesis. I am also grateful to the Department of Employment, Education, Training and Youth affairs for the Australian Postgraduate Award (APA). Last, but by no means least, I am deeply grateful to my family, my husband Jiyuan and my lovely son Tian, for their love, constant understanding, continued support and patience during my study. ill ABSTRACT This thesis describes the development of a synthetic approach to aromatic analogues of himbacine, a potent muscarinc antagonist that is of interest to the study of age-related disease. The studies have focused on strategies towards the lower (or southern) portion of the molecule and methods that involve the Michael reaction to assemble the carbon framework. An improved procedure for preparation of (+)-5-methyl-2(5H)-furanone as a Michael acceptor has been achieved in 51 % overall yield. Various methods of synthesis were investigated towards 2-(2-bromomethylphenyl)acetaldehyde as a Michael donor. The molecule was finally synthesised from isochroman through hydrogen bromide cleavage and oxidation but it was unstable and not suitable as an intermediate. An alternative Michael donor, 2-(2-methoxymethylphenyl)acetaldehyde N,N-dimethylhydrazone was eventually prepared and proved to be a more stable partner,, _j,,.- __ tMvirn dJ-r1 .-.d..,fwr11 f .,-, y/;,7 ~ and suitable intermediate for reaction. Conjugate additionnof' hydrazoner~Jtvith unsaturated ester was studied in model systems and the reaction applied to the above hydrazone and unsaturated lactone partner. A number of advanced intermediates with modified substituents were prepared but all proved difficult and did not undergo the ring closure desired for completion of the synthesis. During the study, the stereochemical outcome of the Michael reaction was determined by spectroscopic methods including the analysis of unexpected products derived from alternative cyclisations. An unusual conformational exchange process was also discovered through n.m.r. analysis of one of the intermediates. This work will provide a base on which future synthetic studies will be developed. iv TABLE OF CONTENTS CERTIFICATE OF ORIGINALITY ACKNOWLEDGEMENTS 11 ABSTRACT 111 TABLE OF CONTENTS iv CHAPTER 1. INTRODUCTION 1.1 Background 1 1.2 Muscarinic Receptor~M 2 Muscarinic Antagonists I 1.3 Alkaloid: Himbacine 4 6 1.4 Structure-Activity Relationships (SAR) 7 1.5 Structural Variants of Himbacine 11 1.6 Approaches to the Total Synthesis of Himbacine 4 Alkaloids 15 1. 7 Aim of the Study 22 CHAPTER 2. RESULTS AND DISCUSSION 23 2.1 Design ofHimbacine Analogue(s) 23 2.2 The Synthesis Plan 24 2.3 Preparation of Michael Acceptor, (+)-5-methyl-2(5H)-furanone 30 25 2.4 Preparation of Michael Donors 30 2.4.1 Attempted preparation of 2-(2-bromomethylphenyl)ethanol 79 31 Oxidation ofindene 78 31 via Claisen rearrangement ofally/ ether 101 35 2.4.2 Preparation of 2-(bromomethylphenyl)acetaldehyde 77 43 V 2.4.3 Preparation of 2-(2-methoxymethylphenyl)acetaldehyde N,N­ dimethylhydrazone 117 47 2.4.4 Preparation of 2-(2-phenoxymethylphenyl)acetaldehyde 120 and its hydrazone 121 49 2.5 Michael Reactions 52 2.5.1 Reactions of enamine 131 with lactone 30 54 2.5.2 Reactions ofhydrazone derivatives 56 2.5.3 Reactions of arylmethyl bromide 141 with methyl crotonate/lactone 30 65 2.6 Preparation of Advanced Intermediates 70 2.6.1 Preparation of aldehyde 148 through solvolysis of hydrazone 139 70 2.6.2 Preparation of acetal 149 76 2.6.3 Preparation of sulfide 153 80 2.6.4 Reactions of compounds 137 and 138 with hydrogen bromide 83 2.6.5 Preparation of aldehyde 158 90 2.7 Ring Closure 97 2.8 Summary and Future Directions 107 CHAPTER 3. EXPERIMENTAL 109 REFERENCES 173 CHAPTER 1. INTRODUCTION 1.1 Background As the world population continues to grow and age, the problem of dementia will become even greater than it is today. 1 Alzheimer's disease (AD) is the most common form of dementia disorder. AD, a devastating neurodegenerative disorder that is characterized by dramatic personality changes, and global cognitive decline currently affects 15 million people worldwide,2 taking more than 100 000 lives each year. 3 Symptoms of age-related diseases are consistent with degeneration of the basal forebrain cholinergic system, i.e. the neural networks in the cortical and hippocampal regions of the brain. In these regions, neurotransmissions are mediated by acetylcholine whose release is regulated by binding to inhibitory M2 muscarinic receptors. Clinical studies of Alzheimer's disease and other age-related illnesses have been restricted largely to subjects that are in advanced stages of dementia, but show that while levels of muscarinic receptors generally remain high elsewhere in the central nervous system 4 (CNS), presynaptic M2 muscarinic receptors in the basal forebrain are depleted. 1.2 Muscarinic Receptors and M2 Muscarinic Antagonists Muscarinic receptors are widely distributed in multiple organs and tissues and are critical to the maintenance of central and peripheral cholinergic neurotransmission.5 Molecular biological studies have demonstrated five distinct subtypes (ml-m5) of muscarinic acetylcholine receptors (mAChR) which share about 70% identity of amino acids in their seven trans-membrane segments.c,.io Each of these subtypes has been found to be localised in discrete areas of the brain or peripheral tissues. s-io Chapter 1 Introduction 2 Me' 1 pirenzepine 2 methoctramine 3 AF-DX 116 4 himbacine 5 4-DAMP 6 Chart 1. Compounds for characterization of muscarinic receptor subtypes M1-~ Muscarinic receptor subtypes have also been divided into four individual groups: M 1, M2, M 3 and M4, that have been characterized 11 by pharmacology using different antagonist affinities. For example, muscarinic M 1 receptors are characterised by a high affinity for pirenzepine 1 (Chart 1) and are found in high density in neuronal tissues and autonomic ganglia, 12 muscarinic M2 receptors have low affinity for pirenzepine 1 and high affinity for methoctramine 2, 13 AF-DX 116 3 14 and himbacine 4, 15 and are located mainly in cardiac tissue to modulate the release of acetylcholine, 16-21 whereas muscarinic Chapter 1 Introduction 3 M3 receptors display low affinity for pirenzepine 1 and high affinity for 4-DAMP 522 and p-fluorohexahydrosiladiphenidol 6,23 and are found in smooth muscles and glands. At present, no selective antagonist is available for the muscarinic M4 receptor subtype.24 Also, the other cloned receptor (m5) is not well characterized owing to a lack of selective ligands. 25 There is some correspondence between the two subtype classifications, but the pharmacologically defined subtypes generally represent combinations of the gene cloned receptor subtype proteins. Evidence has accumulated in recent years for the belief that selective muscarinic blockers might play an important role in the field of AD. For instance, it has been shown that M2 antagonists, such as AF-DX 116 3, enhance the release of acetylcholine in certain brain areas like cortex and hippocampus, both in vitro and in vivo. 26-28 This is due to a blockade of presynaptic receptors (marked as M2 sites in Figure 1) in the cortex and hippocampus receptors which enhances release of acetylcholine (Ach). The use of selective M2 antagonists could therefore be a new strategy to improve memory and learning. According to this concept, a potential therapeutic agent would have to possess good penetration through the blood brain barrier (BBB) and have a high selectivity for M2 versus M 1 receptors, since the drug should not counteract its presynaptic action by blocking postsynaptic M 1 receptors.
Load more

Recommended publications
  • Cell Line Descriptions Geneblazer® M1-NFAT
    Version No.: GeneBLAzer ® Validation Packet Page 1 of 5 01Sep08 Optimization of the GeneBLazer ® M1-NFAT-bla Jurkat Cell Line GeneBLAzer ® M1 NFAT-bla Jurkat Cells Catalog Numbers – K1710 Cell Line Descriptions GeneBLAzer ® M1-NFAT-bla Jurkat cells contain the human Acetylcholine (muscarinic) subtype 1 receptor (M1), (Accession # NM_000738 ) stably integrated into the CellSensor ® NFAT-bla Jurkat cell line. CellSensor ® NFAT-bla Jurkat cells (Cat. no. K1671) contain a beta-lactamase (bla ) reporter gene under control of the Nuclear Factor of Activated T-cells (NFAT) response element. M1-NFAT-bla Jurkat cells are functionally validated for Z’-factor and EC 50 concentrations of carbachol (Figure 1). In addition, GeneBLAzer ® M1-NFAT-bla CHO-K1 cells have been tested for assay performance under variable conditions. Target Description Muscarinic acetylcholine receptors are members of the G protein-coupled receptor (GPCR) superfamily. Muscarinic receptors are widely distributed and mediate the actions of acetylcholine in both the CNS and peripheral tissues. Five muscarinic receptor subtypes have been identified and are referred to as M 1-M5 (1-5). The five genes that encode the muscarinic receptors all belong to the rhodopsin-line family (Family A) and share strong sequence homology but have unique regions located at the amino terminus (extracellular) and in the third intracellular loop. The M 1, M3, and M 5 receptor subtypes couple through the G q/11 class of G-proteins and activate the phopholipase C pathway. Activation of this pathway in turn leads to increases in free intracellular calcium levels as inositol triphosphate mediates release of calcium from the endoplasmic reticulum.
    [Show full text]
  • (12) Patent Application Publication (10) Pub. No.: US 2006/0110449 A1 Lorber Et Al
    US 200601 10449A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2006/0110449 A1 LOrber et al. (43) Pub. Date: May 25, 2006 (54) PHARMACEUTICAL COMPOSITION Publication Classification (76) Inventors: Richard R. Lorber, Scotch Plains, NJ (US); Heribert W. Staudinger, Union, (51) Int. Cl. NJ (US); Robert E. Ward, Summit, NJ A6II 3/473 (2006.01) (US) A6II 3L/24 (2006.01) Correspondence Address: A6IR 9/20 (2006.01) SCHERING-PLOUGH CORPORATION (52) U.S. Cl. ........................... 424/464; 514/290: 514/540 PATENT DEPARTMENT (K-6-1, 1990) 2000 GALLOPNG HILL ROAD KENILWORTH, NJ 07033-0530 (US) (57) ABSTRACT (21) Appl. No.: 11/257,348 (22) Filed: Oct. 24, 2005 The present invention relates to formulations useful for Related U.S. Application Data treating respiratory disorders associated with the production of mucus glycoprotein, skin disorders, and allergic conjunc (60) Provisional application No. 60/622,507, filed on Oct. tivitis while substantially reducing adverse effects associ 27, 2004. Provisional application No. 60/621,783, ated with the administration of non-selective anti-cholin filed on Oct. 25, 2004. ergic agents and methods of use thereof. US 2006/01 10449 A1 May 25, 2006 PHARMACEUTICAL COMPOSITION example, Weinstein and Weinstein (U.S. Pat. No. 6,086,914) describe methods of treating allergic rhinitis using an anti CROSS REFERENCE TO RELATED cholinergic agent with a limited capacity to pass across lipid APPLICATION membranes, such as the blood-brain barrier, in combination with an antihistamine that is limited in both sedating and 0001. This application claims benefit of priority to U.S.
    [Show full text]
  • In Vitro Pharmacology of Clinically Used Central Nervous System-Active Drugs As Inverse H1 Receptor Agonists
    0022-3565/07/3221-172–179$20.00 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 322, No. 1 Copyright © 2007 by The American Society for Pharmacology and Experimental Therapeutics 118869/3215703 JPET 322:172–179, 2007 Printed in U.S.A. In Vitro Pharmacology of Clinically Used Central Nervous System-Active Drugs as Inverse H1 Receptor Agonists R. A. Bakker,1 M. W. Nicholas,2 T. T. Smith, E. S. Burstein, U. Hacksell, H. Timmerman, R. Leurs, M. R. Brann, and D. M. Weiner Department of Medicinal Chemistry, Leiden/Amsterdam Center for Drug Research, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands (R.A.B., H.T., R.L.); ACADIA Pharmaceuticals Inc., San Diego, California (R.A.B., M.W.N., T.T.S., E.S.B., U.H., M.R.B., D.M.W.); and Departments of Pharmacology (M.R.B.), Neurosciences (D.M.W.), and Psychiatry (D.M.W.), University of California, San Diego, California Received January 2, 2007; accepted March 30, 2007 Downloaded from ABSTRACT The human histamine H1 receptor (H1R) is a prototypical G on this screen, we have reported on the identification of 8R- protein-coupled receptor and an important, well characterized lisuride as a potent stereospecific partial H1R agonist (Mol target for the development of antagonists to treat allergic con- Pharmacol 65:538–549, 2004). In contrast, herein we report on jpet.aspetjournals.org ditions. Many neuropsychiatric drugs are also known to po- a large number of varied clinical and chemical classes of drugs tently antagonize this receptor, underlying aspects of their side that are active in the central nervous system that display potent effect profiles.
    [Show full text]
  • TE INI (19 ) United States (12 ) Patent Application Publication ( 10) Pub
    US 20200187851A1TE INI (19 ) United States (12 ) Patent Application Publication ( 10) Pub . No .: US 2020/0187851 A1 Offenbacher et al. (43 ) Pub . Date : Jun . 18 , 2020 ( 54 ) PERIODONTAL DISEASE STRATIFICATION (52 ) U.S. CI. AND USES THEREOF CPC A61B 5/4552 (2013.01 ) ; G16H 20/10 ( 71) Applicant: The University of North Carolina at ( 2018.01) ; A61B 5/7275 ( 2013.01) ; A61B Chapel Hill , Chapel Hill , NC (US ) 5/7264 ( 2013.01 ) ( 72 ) Inventors: Steven Offenbacher, Chapel Hill , NC (US ) ; Thiago Morelli , Durham , NC ( 57 ) ABSTRACT (US ) ; Kevin Lee Moss, Graham , NC ( US ) ; James Douglas Beck , Chapel Described herein are methods of classifying periodontal Hill , NC (US ) patients and individual teeth . For example , disclosed is a method of diagnosing periodontal disease and / or risk of ( 21) Appl. No .: 16 /713,874 tooth loss in a subject that involves classifying teeth into one of 7 classes of periodontal disease. The method can include ( 22 ) Filed : Dec. 13 , 2019 the step of performing a dental examination on a patient and Related U.S. Application Data determining a periodontal profile class ( PPC ) . The method can further include the step of determining for each tooth a ( 60 ) Provisional application No.62 / 780,675 , filed on Dec. Tooth Profile Class ( TPC ) . The PPC and TPC can be used 17 , 2018 together to generate a composite risk score for an individual, which is referred to herein as the Index of Periodontal Risk Publication Classification ( IPR ) . In some embodiments , each stage of the disclosed (51 ) Int. Cl. PPC system is characterized by unique single nucleotide A61B 5/00 ( 2006.01 ) polymorphisms (SNPs ) associated with unique pathways , G16H 20/10 ( 2006.01 ) identifying unique druggable targets for each stage .
    [Show full text]
  • G Protein-Coupled Receptors
    S.P.H. Alexander et al. The Concise Guide to PHARMACOLOGY 2015/16: G protein-coupled receptors. British Journal of Pharmacology (2015) 172, 5744–5869 THE CONCISE GUIDE TO PHARMACOLOGY 2015/16: G protein-coupled receptors Stephen PH Alexander1, Anthony P Davenport2, Eamonn Kelly3, Neil Marrion3, John A Peters4, Helen E Benson5, Elena Faccenda5, Adam J Pawson5, Joanna L Sharman5, Christopher Southan5, Jamie A Davies5 and CGTP Collaborators 1School of Biomedical Sciences, University of Nottingham Medical School, Nottingham, NG7 2UH, UK, 2Clinical Pharmacology Unit, University of Cambridge, Cambridge, CB2 0QQ, UK, 3School of Physiology and Pharmacology, University of Bristol, Bristol, BS8 1TD, UK, 4Neuroscience Division, Medical Education Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, UK, 5Centre for Integrative Physiology, University of Edinburgh, Edinburgh, EH8 9XD, UK Abstract The Concise Guide to PHARMACOLOGY 2015/16 provides concise overviews of the key properties of over 1750 human drug targets with their pharmacology, plus links to an open access knowledgebase of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. The full contents can be found at http://onlinelibrary.wiley.com/doi/ 10.1111/bph.13348/full. G protein-coupled receptors are one of the eight major pharmacological targets into which the Guide is divided, with the others being: ligand-gated ion channels, voltage-gated ion channels, other ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading.
    [Show full text]
  • (Ph OH N N Me O YO O YO
    US 20070265293A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2007/0265293 A1 Boyd et al. (43) Pub. Date: Nov. 15, 2007 (54) (S)-N-METHYLNALTREXONE Publication Classification (76) Inventors: Thomas A. Boyd, Grandview, NY (51) Int. Cl. (US); Howard Wagoner, Warwick, NY A6II 3L/4355 (2006.01) (US); Suketu P. Sanghvi, Kendall Park, A6M II/00 (2006.01) NJ (US); Christopher Verbicky, A6M I5/08 (2006.01) Broadalbin, NY (US); Stephen 39t. 35O C Andruski, Clifton Park, NY (US) (2006.01) A6IP 3L/00 (2006.01) Correspondence Address: St. 4. CR WOLF GREENFIELD & SACKS, P.C. (2006.01) 6OO ATLANTIC AVENUE 3G (i. 308: BOSTON, MA 02210-2206 (US) A6IP 33/02 (2006.01) C07D 489/00 (2006.01) (21) Appl. No.: 11/441,452 (52) U.S. Cl. .............. 514/282; 128/200.23; 128/202.17; (22) Filed: May 25, 2006 546/45 Related U.S. Application Data (57) ABSTRACT This invention relates to S-MNTX, methods of producing (60) Provisional application No. 60/684,570, filed on May S-MNTX, pharmaceutical preparations comprising 25, 2005. S-MNTX and methods for their use. O G M Br Br e (pH OH N N Me O YO O YO OH OH R-MNTX S-MNTX Patent Application Publication Nov. 15, 2007 Sheet 1 of 6 US 2007/0265293 A1 Fig. 1 OH OH Me-N Me-N D / O O -----BBr, O O CHCI NMP, 3 AUTOCLAVE, 70'C OMe OH 1 2 Br OH As GE) G As 69 GOH Me-N ION Me-N -lass O SO EXCHANGE O SO OH OH 3 S-MNTX 1 - OXYCODONE 2 - OXYMORPHONE 3 - ODIDE SALT OF S-MNTX Fig.
    [Show full text]
  • In Gtopdb V.2021.2
    IUPHAR/BPS Guide to Pharmacology CITE https://doi.org/10.2218/gtopdb/F2/2021.2 Acetylcholine receptors (muscarinic) in GtoPdb v.2021.2 Nigel J. M. Birdsall1, Sophie Bradley2, David A. Brown3, Noel J. Buckley4, R.A. John Challiss2, Arthur Christopoulos5, Richard M. Eglen6, Frederick Ehlert7, Christian C. Felder8, Rudolf Hammer9, Heinz J. Kilbinger10, Günter Lambrecht11, Chris Langmead5, Fred Mitchelson12, Ernst Mutschler11, Neil M. Nathanson13, Roy D. Schwarz14, David Thal5, Andrew B. Tobin2, Celine Valant5 and Jurgen Wess15 1. Francis Crick Institute, UK 2. University of Leicester, UK 3. University College London, UK 4. King's College London, UK 5. Monash University, Australia 6. PerkinElmer, UK 7. University of California Irvine, USA 8. Lilly Research Laboratories, USA 9. Nippon Boehringer Ingleheim, Japan 10. University of Mainz, Germany 11. University of Frankfurt, Germany 12. University of Melbourne, Australia 13. University of Washington, USA 14. Pfizer, USA 15. National Institutes of Health, USA Abstract Muscarinic acetylcholine receptors (mAChRs) (nomenclature as agreed by the NC-IUPHAR Subcommittee on Muscarinic Acetylcholine Receptors [50]) are activated by the endogenous agonist acetylcholine. All five (M1-M5) mAChRs are ubiquitously expressed in the human body and are therefore attractive targets for many disorders. Functionally, M1, M3, and M5 mAChRs preferentially couple to Gq/11 proteins, whilst M2 and M4 mAChRs predominantly couple to Gi/o proteins. Both agonists and antagonists of mAChRs are clinically approved drugs, including pilocarpine for the treatment of elevated intra-ocular pressure and glaucoma, and atropine for the treatment of bradycardia and poisoning by muscarinic agents such as organophosphates. I Contents This is a citation summary for Acetylcholine receptors (muscarinic) in the Guide to Pharmacology database (GtoPdb).
    [Show full text]
  • United States Patent (10) Patent No.: US 8,003,794 B2 Boyd Et Al
    USO08003794B2 (12) United States Patent (10) Patent No.: US 8,003,794 B2 Boyd et al. (45) Date of Patent: Aug. 23, 2011 (54) (S)-N-METHYLNALTREXONE 4.385,078 A 5/1983 Onda et al. 4.427,676 A 1, 1984 White et al. (75) Inventors: Thomas A. Boyd, Grandview, NY (US); 4,430,327 A 2, 1984 Frederickson et al. 4,452,775 A 6, 1984 Kent Howard Wagoner, Warwick, NY (US); 4,457.907. A 7/1984 Porter et al. Suketu P. Sanghvi, Kendall Park, NJ 4.462,839 A 7/1984 McGinley et al. (US); Christopher Verbicky, 4,466,968 A 8, 1984 Bernstein Broadalbin, NY (US); Stephen t St. A s 3. Miley al. Andruski, Clifton Park, NY (US) 4,556,552- - - A 12/1985 Porter2 et al.a. 4,606,909 A 8/1986 Bechgaard et al. (73) Assignee: Progenics Pharmaceuticals, Inc., 4,615,885 A 10/1986 Nakagame et al. Tarrytown, NY (US) 4,670.287. A 6/1987 Tsuji et al. 4.675, 189 A 6, 1987 Kent et al. (*) Notice: Subject to any disclaimer, the term of this 4,689,332 A 8/1987 McLaughlin et al. patent is extended or adjusted under 35 2.7868 A SE Se U.S.C. 154(b) by 184 days. 4,765,978 A 8/1988 Abidi et al. 4,806,556 A 2/1989 Portoghese (21) Appl. No.: 12/460,507 4,824,853. A 4, 1989 Walls et al. 4,836,212 A 6, 1989 Schmitt et al. (22) Filed: Jul. 20, 2009 4,837.214 A 6, 1989 Tanaka et al.
    [Show full text]
  • A Straightforward Route to Enantiopure Pyrrolizidines And
    Molecules 2001, 6, 142-193 molecules ISSN 1420-3049 http://www.mdpi.org Review Muscarinic Receptor Agonists and Antagonists Kenneth J. Broadley1 and David R. Kelly2,* 1Division of Pharmacology, Welsh School of Pharmacy and 2Department of Chemistry, Cardiff University, Cathays Park, Cardiff, CF10 3TB, UK *To whom correspondence should be addressed; e-mail: [email protected] Received: 2 August 2000; in revised form 16 January 2001 / Accepted: 16 January 2001 / Published: 28 February 2001 Abstract: A comprehensive review of pharmacological and medical aspects of the muscarinic class of acetylcholine agonists and antagonists is presented. The therapeutic benefits of achieving receptor subtype selectivity are outlined and applications in the treatment of Alzheimer’s disease are discussed. A selection of chemical routes are described, which illustrate contemporary methodology for the synthesis of chiral medicinal compounds (asymmetric synthesis, chiral pool, enzymes). Routes to bicyclic intrannular amines and intramolecular Diels-Alder reactions are highlighted. Keywords: Alzheimer’s disease, nicotine, acetylcholine, arecoline, himbacine, tacrine, cyclostelletamines, intramolecular Diels-Alder reaction, indole alkaloids Contents 1 The Pharmacology of Muscarinic Receptors 1.1 Introduction 1.2 Muscarinic receptor subtypes Molecules 2001, 6 143 2 Pharmacological Effects of Agonists and Therapeutic Applications 2.1 Cardiovascular system 2.2 Gastointestinal tract 2.3 Other smooth muscle 2.4 Glandular secretions 2.5 The eye 2.6 Central nervous
    [Show full text]
  • V10a93-Yin Pgmkr
    Molecular Vision 2004; 10:787-93 <http://www.molvis.org/molvis/v10/a93> ©2004 Molecular Vision Received 22 December 2003 | Accepted 19 August 2004 | Published 13 October 2004 Muscarinic antagonist control of myopia: A molecular search for the M1 receptor in chick George C. Yin, Alex Gentle, Neville A. McBrien Department of Optometry and Vision Sciences, The University of Melbourne, Victoria, Australia Purpose: Pirenzepine, an M1 selective muscarinic antagonist, is effective in slowing the progression of myopia in both humans and experimental animals, including chick. As an M1 selective antagonist, pirenzepine is considered to mediate its effect through M1 receptors. However, there is currently no report of the M1 receptor in chicken. Therefore, if the mechanism of action of pirenzepine is similar across species, either the drug mediates its effect through a non-M1 mecha- nism, or M1 muscarinic receptors are present in chicken. The aim of the present study was to determine whether a genetic template for the M1 receptor was expressed, or even present, in chick. Methods: Polymerase Chain Reaction (PCR), and Southern and northern blotting analyses were used to search for M1 mRNA in chick ocular and brain tissues. PCR and Southern analyses were then used for searching the chick M1 gene and promoter. Appropriate rat positive controls were included throughout the study. Results: Direct mRNA detection by northern analysis showed no evidence of M1 mRNA expression in the chick ocular and brain tissues studied. Identical results were obtained from PCR amplification and were further confirmed by Southern analysis. Similarly, no M1 gene or promoter sequences were detected by PCR or Southern analyses.
    [Show full text]
  • Muscarinic Receptor Functioning and Distribution in The
    Muscarinic receptor GREGOR W. NIETGEN, JOERG SCHMIDT, LUTZ HESSE, CHRISTIAN W. HONEMANN, functioning and MARCEL E. DURIEUX distribution in the eye: molecular basis and implications for clinical diagnosis and therapy The role of neurotransmitters has generated number of receptors (cholinergic, adrenergic considerable interest over the last decade. and others) have been found in all types of Dale's first description in 1914 of the muscarinic ocular tissue: the functional consequence of and nicotinic components of the cholinergic their activation remains elusive but is currently systeml provided an explanation for the effects being investigated with great zeal. Glaucoma of various cholinergic active drugs on the eye. patients are still being treated with pilocarpine G.w. Nietgen J. Schmidt Parasympathetic cholinergic input to the human almost 40 years5 after its introduction to western L. Hesse iris sphincter muscle comes from neurons medicine in 1875.6 The development of specific Zentrum fOr whose axons make up the ciliary nerve, a muscarinic agonists (acetyl-j3-methylcholine) Augenheilkunde branch of the third cranial nerve. Acetylcholine and antagonists (scopolamine) followed. Philipps-Universitat Marburg is released by these neurons onto their target Cholinesterase was discovered in 19267 and Marburg, Germany 8 cells, the smooth muscle surrounding the pupil. named in 1932. At the same time carbachol was C.W. Honemann Muscarinic acetylcholine receptors on the synthesised,9 a drug resistant to cholinesterases M.E. Durieux surface of the muscle cells transduce the with a suitable specificity for glaucoma Departments of chemical signal into a muscle contraction which treatment.IO,ll Over the years various Pharmacology, Anaesthesiology and constricts the pupil.
    [Show full text]
  • (12) Patent Application Publication (10) Pub. No.: US 2009/0076019 A1 Tyers Et Al
    US 20090076019A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2009/0076019 A1 Tyers et al. (43) Pub. Date: Mar. 19, 2009 (54) METHODS FOR TREATING Publication Classification NEUROLOGICAL DISORDERS OR DAMAGE (51) Int. Cl. Inventors: Mike Tyers, Toronto (CA); Phedias A63/496 (2006.01) (75) CI2O 1/02 (2006.01) Diamandis, Toronto (CA); Peter B. A6II 3/445 (2006.01) Dirks, Toronto (CA) A63/64 (2006.01) Correspondence Address: A6IP 25/00 (2006.01) HOWSON AND HOWSON A6IP 25/6 (2006.01) SUITE 210,501 OFFICE CENTER DRIVE A6IP 25/18 (2006.01) FT WASHINGTON, PA 19034 (US) (52) U.S. Cl. ...................... 514/252.13:435/29: 514/317; 514f613 (73) Assignees: Mount Sinai Hospital, Toronto (CA); HSC Research and Development Limited (57) ABSTRACT Partnership, Toronto (CA) A clonogenic neurosphere assay is described that carries out high throughput screens (HTS) to identify potent and/or (21) Appl. No.: 11/871,562 selective modulators of proliferation, differentiation and/or renewal of neural precursor cells, neural progenitor cells and/ (22) Filed: Oct. 12, 2007 or self-renewing and multipotent neural stem cells (NSCs). Compositions comprising the identified modulators and Related U.S. Application Data methods of using the modulators and compositions, in par (60) Provisional application No. 60/851,615, filed on Oct. ticular to treat neurological disorders (e.g. brain or CNS can 13, 2006. cer) or damage are also disclosed. Neurosphere Stein Progenitor Differentiated eEE eEE t Prolifefatic Assay Patent Application Publication Mar. 19, 2009 Sheet 1 of 26 US 2009/0076019 A1 Figure 1 Neurosphere Progenitor O Defeitiated e CE M.
    [Show full text]