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Synthesis of Novel Allosteric Agonists and Allosteric Modulators for Nicotinic Acetylcholine Receptors

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Synthesis of Novel Allosteric Agonists and Allosteric Modulators for Nicotinic Acetylcholine Receptors Synthesis of Novel Allosteric Agonists and Allosteric Modulators for Nicotinic Acetylcholine Receptors A dissertation presented by Persis Dhankher Supervisor: Dr. Tom Sheppard [November 2013] in partial fulfilment of the requirements for the award of the degree of DOCTOR OF PHILOSOPHY at UNIVERSITY COLLEGE LONDON Department of Chemistry Christopher Ingold Laboratories University College London 20 Gordon Street WC1H 0AJ London Declaration I, Persis Dhankher, confirm that the work presented in this thesis is my own. Where information is derived from other sources, I confirm that it has been indicated and acknowledged. ………………………………. 2 Contents Declaration Abstract Contents Abbreviations Acknowledgements Chapter 1 ................................................................................................................................ 11 Introduction ...................................................................................................................... 11 1.1 Nicotinic Acetylcholine Receptors ...................................................................... 11 1.2 Structure and Function of nAChRs ................................................................... 13 1.2.1 Subunit Subtypes ........................................................................................... 13 1.2.2 Subunit structure of nAChRs ......................................................................... 14 1.3 Heteromeric and Homomeric Receptors ........................................................... 14 1.4 . Orthosteric and Allosteric binding site ............................................................ 15 1.5 Alzheimer’s Disease (AD) .................................................................................... 16 1.5.1 Current drug treatments for Alzheimer’s Disease in USA (FDA) and UK ... 17 1.6 Non-selective compounds for nAChRs ............................................................... 18 1.6.1 Agonists ......................................................................................................... 18 1.6.2 Antagonists .................................................................................................... 19 1.7 Ligands selective for α7 nAChRs ........................................................................ 20 1.7.1 Agonists ......................................................................................................... 20 1.7.2 Antagonists .................................................................................................... 21 1.7.3 Allosteric modulation on α7-nAChRs ........................................................... 22 1.7.3.1 PAMs of α7 nAChRs ......................................................................... 23 1.7.3.2 Type I and Type II PAMs .............................................................. 24 1.8 Advantages of α7 PAMs over α7 agonists .......................................................... 26 Chapter 2 ................................................................................................................................ 27 2 Synthesis of 4BP-TQS Analogues and Pharmacological Study on α7 nAChRs ........... 27 2.1 Previous work ....................................................................................................... 27 2.1.1 Pavarov reaction ................................................................................................... 31 2.2 Aim and Objectives .............................................................................................. 33 2.3 Results and Discussion ......................................................................................... 34 3 2.4 Biological testing results (work conducted by JasKiran Gill and Neil Millar, at UCL Pharmacology) .................................................................................................... 41 2.4.1 PAM activity at the α7 nAChR ...................................................................... 45 2.4.2 Antagonism by 4FP-TQS 32b of 4BP-TQS 28b Evoked Responses ............. 49 2.4.3 Influence of the Transmembrane M253L Mutation ....................................... 51 2.4.4 Conclusion ..................................................................................................... 52 2.5 Synthesis of methylated TQS compounds .......................................................... 53 2.6.1 Synthetic route towards methyl substituted benzaldehydes. .......................... 55 2.6.2 Biological test results of methylated TQS compounds (work conducted by JasKiran Gill and Neil Millar, UCL Pharmacology) ..................................................... 61 2.6.3 Conclusion ..................................................................................................... 67 2.6.4 Future Work ................................................................................................... 68 2.7 Additional examples of p-substituted TQS compounds.................................... 69 2.7.1 Biological test results (conducted by JasKiran Gill and Neil Millar, UCL Pharmacology) ............................................................................................................... 70 2.7.2 Irradiation study ............................................................................................. 72 2.8 Heteroaromatic Benzaldehyde Analogues ......................................................... 73 2.8.1 Conclusion ..................................................................................................... 75 2.9 Modification of Sulphanilamide Component for the Synthesis of 4BP-TQS Analogues .......................................................................................................................... 78 2.10 Modification of the cyclopenta- ring component of 4BP-TQS ......................... 80 2.10.1 Synthesis of furano- and pyrano- quinolines ................................................. 80 2.10.2 Biological test results (conducted by JasKiran Gill and Neil Millar, UCL Pharmacology). .............................................................................................................. 85 2.11 Conclusions/Future Work ................................................................................... 86 3 Ligands for α4β2 nAChRs ............................................................................................. 88 3.1 Agonists ................................................................................................................. 88 3.1.1 Antagonists .................................................................................................... 89 3.1.2 PAMs ............................................................................................................. 90 3.2 Synthesis of Desformylflustrabromine (DfBr) analogues for α4β2 nAChRs .. 92 3.2.1 Aim ................................................................................................................ 92 3.3 Results and Discussion ......................................................................................... 94 3.3.1 Directing group approach for regioselective C-2 allylation ........................... 94 3.3.2 Non-directing group approach for regioselective allylation ........................ 101 3.3.2.1 Optimisation of diallylindolenine formation .............................. 105 4 3.4 Mechanism .......................................................................................................... 109 3.5 Substrate scope of diallylation (and monoallylation) of substituted indoles 111 3.6 Reactions of substituted diallyl indolenine ...................................................... 118 3.6.1 Reaction with Methyl Chloroformate .......................................................... 122 Table 17 ....................................................................................................................... 123 3.6.2 Asymmetric Proline Catalysed Mannich Reaction ...................................... 124 3.6.2.1 Optimisation ................................................................................. 125 3.6.2.2 Proline catalysed asymmetric Mannich reaction ...................... 126 3.6.2.3 Reaction mechanism .................................................................... 128 3.7 Conclusion/Future Work .................................................................................. 129 4 Experimental ................................................................................................................ 132 4.1 General Methods and Experimentation ........................................................... 132 5. References ........................................................................................................................ 242 5 Abstract In healthy individuals, the α7 and α4β2 nAChRs are concentrated in regions of the brain involved with learning, cognition and memory, which are relevant to diseases such as Alzheimer’s disease. Hence, these receptors have become significant from a pharmacological and drug discovery perspective. The tetrahydroquinoline compound 4BP-TQS has been reported to act as a potent allosteric agonist on the α7 nAChR. The natural product desformylflustrabromine is able to act as a positive allosteric modulator (PAM) on the α4β2 nAChR. This thesis describes the development of synthetic routes directed towards 4BP-TQS and desformyflustrabromine analogues, and their pharmacological effects on α7 and α4β2 nAChRs. In the first half of the project a total of 51
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