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Selective Monoamine-Oxidase Inhibition in Man: a Biochemical and Pharmacological Study

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Selective Monoamine-Oxidase Inhibition in Man: a Biochemical and Pharmacological Study SELECTIVE MONOAMINE-OXIDASE INHIBITION IN MAN: A BIOCHEMICAL AND PHARMACOLOGICAL STUDY Submitted for the degree of Doctor of Philosophy by John David Elsworth Institute of Obstetrics and Gynaecology University of London 1980 ABSTRACT OF THESIS Much of the work described in this thesis centres on the selective MAO-B inhibitor (-)-deprenyl. Its inhibitory action was determined in vitro and a 10-6 M concentration was found to produce optimum selectivity between MAO-A and MAO-B. This concentration is approximately equal to 10 mg of the drug evenly distributed throughout an average body water space. When administered to normal volunteers, this dose of deprenyl produced rapid inhibition of platelet MAO activity. Urinary phenylethylamine, phenylacetic acid and dopamine were monitored during treatment; phenylethylamine output became, elevated only when platelet activity was inhibited by more than about 80%. An increase in phenylethylamine excretion appears to provide a good index of overall body MAO-B inhibition. In normal and parkinsonian subjects, deprenyl is free from the tyramine and phenylethylamine-potentiating effects on blood pressure characteristic of other irreversible MAO inhibitors. This lack of "cheese effect" persisted even during chronic deprenyl treatment. Clinical studies confirmed that deprenyl is a useful, if limited, adjuvant to L-dopa therapy in Parkinson's disease. Although individual variation in susceptiblity to platelet enzyme inhibition was observed, such differences had no clinical counterpart; in any case, activity rapidly ceased with a dosage regimen of 10 mg daily. As in controls, deprenyl raised urinary phenylethylamine concentrations in parkinsonian patients, apart from those simultaneously receiving a decarboxylase inhibitor. Despite wide variation in the distribution of MAO A and B activity in the body, dopamine was oxidised vigorously in all tissues. In the brain the striatum and accumbens contained the lowest A:B ratio and dopamine oxidation in these regions was most susceptible to deprenyl inhibition.. TMH was identified as a novel substrate for MAO-B in man. Deprenyl was shown to be converted in vivo to methamphetamine and amphetamine. The antiparkinsonian properties of the drug are unlikely to stem from the pharmacological effects of these metabolites. 2 Contents Page 1• Title page 2 Abstract of thesis • 3 Contents 7 Tables and Figures 9 Acknowledgements 10 Abbreviations 11 Chapter One - General introduction 11 (i) Discovery of MAO 11 (ii) Substrate specificity 12 (iii) Other requirements for activity 12 (iv) Distribution 12 (v) Inhibitors of MAO 14 (vi) Function of MAO 16 (vii) Multiple forms of MAO 18 (viii) Selective inhibitors of MAO 20 (ix) The potential of selective inhibitors 22 Chapter Two - Methods 22 (i) Sample preparation 22 (a) Urine 22 (b) Plasma 22 (c) Platelets 23 (d) Tissue 23 (ii) MAO method 23 (a) Validity of the assay 25 (b) Assay without added inhibitor 26 (c) Assay with added inhibitor 26 (d) Separation of products from substrate 26 (iii) PEA method 27 (a) Extraction 27 (b) Derivatization 27 (c) Analysis 28 (iv) PAA method 28 (a) Plasma extraction 29 (b) Urine extraction 29 (c) Derivatization 30 (d) Analysis Contents (cont.) Page 30 (v) DA method 30 (a) Extraction 31 (b) Derivatization 31 (c) Analysis 32 (vi) Protein estimation 33 Chapter Three - Deprenyl and the "cheese effect" 33 (i) The "cheese effect" 35 (ii) Paradoxical absence of the "cheese effect" 37 (iii) Selective MAO inhibitors and the "cheese effect" 38 Methods 38 (i) Oral amine pressor tests 40 (ii) Urinary PEA, PAA and DA excretion before and after deprenyl 40 (iii) Effect of deprenyl on intestinal and platelet MAO activity in vitro 40 (iv) Effect of deprenyl on the metabolism of orally ingested amines 41 (v) Relationship between PEA excretion and MAO inhibition 41 Results 41 (i) TYR pressor test 45 (ii) PEA pressor test 45 (iii) Inhibition'of MAO by deprenyl 45 (a) In vivo 45 (b) In vitro 51 (iv) Deprenyl and PEA excretion 51 (a) Effect on free amine 51 (b) Effect on conjugated amine 51 (v) Relationship between MAO inhibition and PEA excretion 51 (vi) TYR metabolism after MAO inhibition 56 (vii) PEA metabolism after MAO inhibition 56 (viii) Effect of deprenyl on PAA 56 (a) Plasma concentration 56 (b) Urinary concentration 56 (ix) Effect of deprenyl on DA excretion 56 Discussion Contents (cont.) Page 67 Chapter Four - Depreny] in Parkinson's disease 67 (i) Aetiology 67 (ii) Pathology 68 (iii) Treatment 68 (a) L-dopa 69 (b) Other forms of treatment 70 (c) MAO inhibitors 72 Methods 72 (i) Clinical 73 (ii) Biochemical 73 Results 73 (i) Clinical 75 (ii) Biochemical 83 Discussion 90 Chapter Five - The effect of deprenyl on DA oxidation in human brain and peripheral tissues 90 (i) MAO in brain 91 (ii) Mixed substrate experiments 92 Materials 92 Methods 92 (i) Collection of material 93 (ii) Dissection of brains 93 (iii) Homogenization 93 (iv) MAO assay 95 Results 100 Discussion 105 Chapter Six - The metabolism of deprenyl 105 Introduction 107 Materials 107 Methods 107 (i) Determination of methamphetamine and amphetamine 108 (ii) Deprenyl assay 108 (iii) Plasma MAO inhibitor assay 110 (iv) Alteration of urinary pH 110 (v) Substitution of deprenyl for methamphetamine and amphetamine Contents (cont.) Page 111 Results 111 (i) GC-MS assay for methamphetamine and amphetamine 111 (ii) Quantification of deprenyl metabolism 111 (iii) The contribution of deprenyl metabolites to its therapeutic action '_15 Discussion 121 Chapter Seven - TMH as a MAO-B substrate in man 121 (i) General introduction 121 (ii) Histamine as a central neurotransmitter 123 (iii) Histamine metabolism 126 (iv) The importance of TMH 128 (v) TMH as a substrate for MAO 129 Materials 130 Methods 130 (i) Direct assay of 3H-TMH oxidation 130 (ii) The effect of deprenyl on 3H-TMH oxidation 130 (iii) Substrate competition between PEA or SHT and TMH 131 (iv) Counting and extraction efficiencies 131 Results 134 Discussion 140 Chapter Eight - General discussion 143 References Publications Tables and Figures Page 13 Figure 1:1 Structures of some MAO inhibitors 15 Figure 1:2 The relationship between some MAO substrates 19 Table 1:1 Specificity of some monoamine oxidase substrates 24 Figure 2:1 Effect of enzyme concentration on reaction velocity 42 Table 3:1 To show response of healthy normal volunteers to oral TYR 43 Figure 3:1 Effect of deprenyl on the pressor response to oral TYR 44 Table 3:2 To show response of patients with Parkinson's disease to oral TYR 46 Figure 3:2 Showing changes in platelet MAO activity and PEA excretion in volunteer 1 receiving deprenyl 47 Figure 3:3 Showing changes in platelet MAO activity and PEA excretion in volunteer 2 receiving deprenyl 48 Figure 3:4 Showing changes in platelet MAO activity and PEA excretion in volunteer 3 receiving deprenyl 49 Figure 3:5 Showing changes in platelet MAO activity and PEA excretion in volunteer 4 receiving deprenyl 50 Figure 3:6 In vitro deprenyl inhibition of intestine and platelet MAO 52 Table 3:3 Effect of deprenyl on PEA excretion in normals 53 Table 3:4 Showing the variation in free PEA excretion in normals 54 Table 3:5 Comparing the effect of deprenyl on the excretion of free and conjugated PEA 55 Table 3:6 Relationship between platelet MAO activity and PEA excretion 57 Table 3:7 Effect of deprenyl on PEA and hydroxyphenylacetic acid excretion after PEA ingestion 58 Table 3:8 Effect of deprenyl on plasma PAA concentration 59 Table 3:9 Effect of deprenyl on urinary PAA concentration 60 Table 3:10 Effect of deprenyl on urinary DA excretion 74 Table 4:1 The response of "on-off" disabilities to deprenyl 76 Table 4:2 Frequency of side-effects 77 Table 4:3 Effect of deprenyl on platelet MAO activity and parkinsonism 79 Figure 4:1 Time course of inhibition of platelet MAO by oral deprenyl 81 Table 4:4 Free urinary excretion of PEA in Parkinson's disease 82 Table 4:5 Effect of carbidopa on free PEA excretion in Parkinson's disease 7 Tables and Figures (cont.) Page 84 Table 4:6 Effect of deprenyl on free PAA excretion in Parkinsonians 94 Figure 5:1 Location of coronal section of brain which reveals the nucleus accumbens 96 Figure 5:2 Comparison of deprenyl inhibition of PEA and 5HT oxidation by human caudate 97 Table 5:1 5HT, PEA and DA-oxidising activities in different regions of human brain and inhibition of DA oxidation by 10-6 M deprenyl 98 Table 5:2 5HT, PEA and DA-oxidising activities in various peripheral tissues and inhibition of DA oxidation by 10-6 M deprenyl 99 Figure 5:3 Lineweaver-Burk plots to compare the Km values of placenta and platelet with DA as substrate 106 Figure 6:1 Structures of deprenyl, methamphetamine and amphetamine 109 Table 6:1 Comparitive electron-capturing ability of pen tafluorobenzamides 112 Figure 6:2 Showing typical traces obtained in the GC-MS assay of methamphetamine and amphetamine 113 Table 6:2 Urinary output of methamphetamine and amphetamine in normal subjects 114 Table 6:3 The presence of a MAO inhibitory substance in plasma after deprenyl administration 116 Table 6:4 The effect of urinary pH on methamphetamine and amphetamine excretion in parkinsonian patients 124 Figure 7:1 Pathways of histamine metabolism 132 Figure 7:2 TLC analysis of 3H-TMH metabolism to 3H-MIAA by human liver 133 Figure 7:3 The sensitivity of PEA and TMH oxidation to deprenyl inhibition 135 Figure 7:4 Competitive inhibition of PEA oxidation by TMH 136 Figure 7:5 Effect of TMH on SHT oxidation 8 Acknowledgements I should like to thank Professor Sandler particularly, for all of his advice during my stay at the laboratory.
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