Molecular Mimicry of Anti-migraine Drugs with the Neurotransmitters, Dopamine (DA) & Serotonin (5-HT) and its Role in the Treatment of Migraine A thesis submitted in partial fulfilment of the requirements for the Degree of Master of Science in Biochemistry In the School of Physical and Chemical Sciences at the University of Canterbury New Zealand By Nancy Joy University of Canterbury 2019 Acknowledgements Special thanks to my supervisor Prof. Ian. C. Shaw for all the discussions to support my thesis and fun lunch outs with our research group team members, who also supported me with molecular modelling guidance especially by Sam and Hector. Special mention to Rachel for taking the extra effort in booking our team meetings online David Zehms for helping me out in reviewing my thesis documents and Parvesh for the humorous talks and making our discussions fun filled moments. Key words Molecular mimicry, serotonin receptors, dopamine receptors, serotonin, dopamine, tyramine, monoaminergic neurons, migraine, migraine treatment, G protein-coupled receptors, neurotransmission, synaptic regulatory receptors and transporters, nociception, nociceptive afferents, neurovascular disorders, brain nuclei, trigeminal nervous system, trigeminal ganglion, vasoactive biochemicals and neuropeptides, insilico molecular modelling. Dedicated to the fond memories of my past professional life which shaped me to be who I am today, to my family & loved ones who have supported me through my struggles, to my aspirations to be a successful professional, and to my dreams: to be a committed family person, a contributor to the society by climbing the ladder of science and thus becoming a high achiever in life with the help of all my supporters! Abbreviations AA Amino acid AD Aldehyde dehydrogenase AP Action potential β2AR β2 adrenergic receptors β-AR β-Arrestin BBB Blood brain barrier CGRP Calcitonin gene-related peptide CM Chronic migraine CNS Central nervous system CTTH Chronic tension-type headache D1 D1 subtype of the dopamine receptors D2 D2 subtype of the dopamine receptors DA Dopamine DHE Dihydroergotamine ERK Extracellular signal–regulated kinases ERM Ergotamine G protein Guanine nucleotide binding protein G score Glide score GABA gamma-Aminobutyric acid GIRKs G protein-coupled inwardly-rectifying potassium channels GPCR G protein-coupled receptors GPCRs G protein-coupled receptors GPs General practitioners GRKs G protein-coupled receptor kinases 5-HIAA 5-Hydroxy indole acetic acid 5-HT 5-Hydroxytryptamine (serotonin) 5-HTP 5-Hydroxytryptophan 5-HTRs 5-Hydroxytryptamine receptors (serotonin receptors) IHS International Headache Society LBC Ligand binding cleft LGICs Ligand-gated Ion Channels MAO Monoamine oxidase MAPK Mitogen activated protein kinases MOA Mode of Action MRI Magnetic resonance imaging NE Noradrenaline (Norepinephrine) NO Nitric Oxide NSAIDs Non-Steroid Anti-Inflammatory Drugs PACAP Pituitary adenylate-cyclase activating peptide PAG Periaqueductal gray PDB Protein Data Bank RVMM Rostral ventromedial medulla SERT Serotonin reuptake transporters SSS Superior sagittal sinus STT Spinothalamic tract TAAR1 Trace amine-associated receptor 1 TH Tryptophan hydroxylase TRP Tryptophan TRY Tryptamine VIP Vasoactive intestinal peptide Table of Contents 1 INTRODUCTION ..................................................................................................................................... 14 1.1 BACKGROUND ......................................................................................................................................... 14 History ............................................................................................................................................. 15 Current concepts and pathophysiology of migraine ....................................................................... 17 Migraine’s link to specific foods and the structural analogy of dietary amino acids to neurotransmitters in migraine ..................................................................................................................... 19 The Prevalence of Migraine ............................................................................................................ 23 1.2 MIGRAINE AND ITS TREATMENT .................................................................................................................. 25 Types of migraine ............................................................................................................................ 25 Treatment ....................................................................................................................................... 27 Current treatment success with anti-migraine treatment .............................................................. 31 1.3 THE ROLE OF NEUROTRANSMITTERS IN MIGRAINE ........................................................................................... 34 Neurotransmitters in synapses ....................................................................................................... 34 5-HT biosynthesis and degradation ................................................................................................ 37 5-HT & DA receptors and their subtypes ......................................................................................... 39 Can anti-migraine drugs act at 5-HT/DA receptors ........................................................................ 40 Is there any rationale behind usage of β-blockers, anticonvulsants, NSAIDs and Vitamin-B’s in migraine treatment? .................................................................................................................................... 41 Migraine links to 5-HT and DA ........................................................................................................ 41 1.4 UNDERSTANDING THE PATHOGENESIS AND NOCICEPTION IN MIGRAINE ............................................................... 46 How anti-migraine agents resolve pain in migraine? ..................................................................... 47 Brain stem nuclei as pain modulation centres ................................................................................ 47 Monoaminergic system in brain nuclei ........................................................................................... 48 Deactivation of nociception in migraine by 5-HTRs ........................................................................ 51 Other predisposing factors in migraine: role of DA lookalike ‘tyramine’ ........................................ 52 Genetic factors ................................................................................................................................ 53 Role of monoamines and their receptors in Migraine .................................................................... 55 Role of vasoactive biochemicals and neuropeptides in migraine ................................................... 61 Nitric oxide (NO) donors and neuropeptide vasodilators as triggers of migraine .......................... 63 Neurobiological events associated with migraine symptoms .................................................... 64 1.5 KNOWN SIGNALLING PATHWAYS OF SEROTONIN ............................................................................................. 65 Serotonin and its receptors ............................................................................................................. 65 Early discovery of Serotonin ............................................................................................................ 65 Early discovery of 5-HTRs ................................................................................................................ 66 5-HTR signalling mechanism ........................................................................................................... 66 5-HTR signalling via β-arrestin mediated pathway ......................................................................... 68 G protein mediated pathways ........................................................................................................ 70 1.6 AIMS AND OBJECTIVES OF THE RESEARCH ...................................................................................................... 72 Aims of the research ....................................................................................................................... 72 Research objectives & study design ................................................................................................ 72 1.7 RESEARCH HYPOTHESIS IN RELATION TO THE STRUCTURAL ANALOGY CONCEPTS ..................................................... 73 1.8 METHODS .............................................................................................................................................. 74 1.9 OVERVIEW OF ‘GLIDE’ PROGRAM AND ‘MAESTRO’ INTERFACE FROM SCHRÖDINGER PLATFORM............................... 74 Glide ................................................................................................................................................ 75 Glide: Protocols ............................................................................................................................... 75 1.10 LIGAND DOCKING EXPERIMENTS USING SCHRÖDINGER ..................................................................................... 78 2 EXPERIMENT RESULTS ..........................................................................................................................