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  • C H E M I C A L
  • S Y N T H E S I S ,
  • D I S P O S I T I O N
  • A N D

  • M E T A B O L I S M
  • O F
  • D O P A M I N E
  • A N D

  • N O R A D R E N A L I N E
  • S U L P H A T E S

BARBARA ALEKSANDRA OSIKOWSKA
A thesis submitted for the degree of
Doctor of Philosophy to the University of London

December 1983

-

2

-

ABSTRACT
The existence of an enzymatic pathway which is capable of sulphating the catecholamine neurotransmitters has been known for over four

  • decades.
  • The importance of this metabolic pathway and its overall

contribution to the enzymatic breakdown of these neurotransmitters has generally received less attention than deamination and JKmethylation. The aim of this work was to synthesise authentic dopamine and noradrenaline ^-sulphates, for use as standards in studies on the disposition and metabolism of these important products of dopamine and noradrenaline metabolism.

  • 1.
  • Three products resulted from chemical sulphonation of dopamine:

dopamine 3-0-sulphate, dopamine 4-0-sulphate and dopamine 6-sulphonic

acid.

  • 2.
  • Because all three products of dopamine sulphonation are isomeric,

chemically similar organic acids and could not be distinguished by analytical techiques such as elemental analysis, ultraviolet spectroscopy and infrared spectroscopy, high performance liquid chromatography was employed for the separation and purification of these products, and nuclear magnetic resonance spectroscopy was considered to be the only technique powerful enough to distinguish between these isomers.

  • 3.
  • Noradrenaline 3- and 4-0-sulphates were isolated from a one-step

  • They were separated, purified and characterised
  • synthetic reaction.

using techniques applied for the synthesis and separation of dopamine ^-sulphates.

-

3

-

4. human urine before and following L-dopa administration and in multiple urine samples from a single subject. Both dopamine O-sulphates were
The disposition of dopamine 3- and 4-0-sulphates was investigated in present in urine under physiological conditions and after L-dopa; however, dopamine 3-0-sulphate was the major urinary conjugate in both circumstances.

5. were investigated in rabbit brain, heart, kidney, liver, spleen and small intestine. Dopamine O-sulphates were not detected in any of the tissues with the method of analysis used; both noradrenaline O^-sulphate isomers were present in the above tissues in ratios depending on the animal and tissue investigated. In tissue homogenates of one
The disposition of dopamine and noradrenaline 3- and 4-0-sulphates rabbit, noradrenaline 4-0-sulphate was not detected. 6 . Experiments investigating the in vitro metabolism of dopamine and noradrenaline O-sulphates showed that the aforementioned compounds were substrates for dopamine conversion of dopamine to noradrenaline. following incubation of dopamine -hydroxylase with dopamine

3

-hydroxylase, the enzyme responsible for the
Two products were formed

3

O-sulphates, namely free noradrenaline and noradrenaline ()-sulphates. In the presence of active dopamine 3 -hydroxylase in the reaction

  • mixture noradrenaline O-sulphates yielded free noradrenaline.
  • The

effects of a dopamine were also investigated.

3

-hydroxylase inhibitor on the above reactions
7. Observations in both experimental animals and man suggest that there may be important interindividual variations in the extent of 4-0- sulphation of these amines, the underlying basis for which cannot at present be explained.

-

4

-

ACKNOWLEDGEMENTS
I would like to thank all those whose help in this project made its completion possible.
I am grateful to Professors P.S. Sever and W.S. Peart for allowing me to carry out this work in their departments.
Professor P.S. Sever and Dr. J. Idle provided help, new ideas, continuous encouragement, criticism and friendship.
Dr. F Swinbourne assisted in providing facilities for nuclear magnetic resonance spectroscopy and helped in the interpretation of the spectra.
I would also like to express my thanks to the following:
Mr. R. Mattin for his technical assistance, Miss G. Bartlett for typing the thesis and Drs. R. Unwin and S. Thom for proof-reading.
I am grateful to all my friends at St. Mary's Hospital Medical
School, past and present, whose friendship and encouragement allowed the satisfactory completion of this thesis.
The work was generously supported by the Wellcome Trust.

I reserve final thanks for my husband and my parents, whose support and understanding given freely through the duration of this work I could never fully return.

-

5

-

CONTENTS
Page
ABBREVIATIONS

LIST OF TABLES LIST OF FIGURES

6

7

9

CHAPTER:
INTRODUCTION

... 12

2345

6

STUDIES ON THE CHEMICAL SULPHONATION OF DOPAMINE AND NORADRENALINE

  • ...
  • 52

DISPOSITION OF DOPAMINE O-SULPHATES IN HUMAN URINE

98

DISPOSITION OF NORADRENALINE 3- AND 4-0-

  • SULPHATES IN RABBIT TISSUES
  • ...
  • 116

FURTHER METABOLISM OF DOPAMINE AND

  • NORADRENALINE SULPHATES
  • ...

...
137 166
DISCUSSION AND CONCLUDING REMARKS
BIBLIOGRAPHY

... 183

RELEVANT PUBLICATIONS

...

212

ABBREVIATIONS COMT DA catechol ()-methyl transferase dopamine

DA 3-0-S04

dopamine 3-0-sulphate dopamine 4-0-sulphate
DA 4-0-S0.

  • -
  • 4

  • DBH
  • dopamine

3

-hydroxylase
3,4-dihydroxyphenylglycol dihydroxyphenylalan ine dihydroxyphenylacetic acid high performance liquid chromatography infrared
DHP6 dopa DOPAC h.p.1.c.

I.R.

monoamine oxidase
MAO
3-methoxy-4-hydroxyphenylglycol
MHPG noradrenaline
NA noradrenaline 3-0-sulphate noradrenaline 4-0-sulphate nuclear magnetic resonance
NA 3-0-S04 NA 4-0-S04

n.m.r.

  • PAP
  • 3'-phosphoadenosine-5'-phosphate

3‘-phosphoadenosine-5'-phosphosulphate phenylethanolamine-Tf-methyltransferase inorganic phosphate
PAPS PNMT PP.

l

phenolsulphotransferase standard deviation
PST S.D. U.V. VMA ultraviolet 4-hydroxy-3-methoxymandelic acid

-

7

-

LIST OF TABLES 1.1 1.2
Plasma catecholamines (pg/ml)

... 24

Percentage increment in plasma noradrenaline and adrenaline with various stimuli

  • ...
  • 28

2.1

2.2
Products of reactions of various sulphonating agents with dopamine at various temperatures

  • ...
  • 65

Products of sulphonation of noradrenaline with H^SO^ at various temperatures and time intervals
79

83
2.3 2.4
Products of reaction of chlorosulphonic acid with noradrenaline at various time intervals Products of reaction of chlorosulphonic acid

  • with noradrenaline:
  • effect of varying

  • reaction mixture composition
  • ...

... ...
85
106 Ill
3.1 3.2 3.3 4.1 4.2 4.3 4.4
Dopamine 0-sulphate content in urine under physiological conditions Dopamine ^-sulphate isomers in urine following oral administration of L-dopa (0.5 g) Recovery of orally administered L-dopa (0.5 g) in 24 h urine as dopamine 3- and 4-0-sulphates Noradrenaline 3- and 4-0-sulphates in rabbit brain tissue

... 112 ... 121

Noradrenaline 3- and 4-0-sulphates in rabbit heart tissue
... ...
123 125
Noradrenaline 3- and 4-0-sulphates in rabbit kidney tissue Noradrenaline 3- and 4-0-sulphates in rabbit

... 127

spleen tissue

Noradrenaline 3- and 4-0-sulphates in rabbit

  • liver tissue
  • 129

131 146
Noradrenaline 3- and 4-0-sulphates in rabbit small intestine tissue Dopamine 4-0-sulphate incubation with D$H at different time intervals Dopamine 3-0-sulphate incubation with D$H at
147

147 149 different time intervals Kinetic study of D$H with dopamine as the substrate Kinetic study of D$H with dopamine 4-0-sulphate as the substrate Concentrations of free noradrenaline formed during incubation of dopamine 4-0-sulphate with D3H in the absence or presence of fusaric acid Products formed by the incubation of dopamine 4-0- sulphate with Df3H
151 152 153
Kinetic study of DBH with dopamine 3-0-sulphate as the substrate Concentrations of free noradrenaline formed during incubation of dopamine 3-0-sulphate with DBH in the absence or presence of fusaric acid Products formed by the incubation of dopamine 3-0- sulphate with D^H
155 156
Noradrenaline 4-0-sulphate incubation in the

  • presence of active D$H
  • ...
  • ...

Noradrenaline 3-0-sulphate incubation in the presence of active D&H

-

9

-

L1ST OF FIGURES

  • 1.1
  • The biosynthesis of dopamine, noradrenaline and

  • adrenaline
  • 15

1.2

Metabolic routes of dopamine, noradrenaline and adrenaline

20

2.1 2.2
Products of chemical sulphonation of dopamine H.p.l.c. chromatogram of products formed during chemical sulphonation of dopamine ...
67

68

  • 2.3
  • 250 MHz *H n.m.r. spectrum (aromatic region)

of dopamine 6-sulphonic acid (product I, bottom),

including expanded spectrum (top) ...
13
71 72 75
2.4 2.5 2.6

  • Off-resonance decoupled
  • C n.m.r. spectrum of

dopamine 6-sulphonic acid

  • 250 MHz
  • n.m.r. spectrum of dopamine 4-0-

sulphate (product II) 250 MHz *H n.m.r. spectrum of dopamine 3-0- sulphate (product III)
77

2.7 2.8
Products of chemical sulphonation of noradrenaline H.p.l.c. chromatogram of products formed during chemical sulphonation of noradrenaline by chlorosulphonic acid

88

89 91

  • 2.9
  • 250 MHz *H n.m.r. spectrum of noradrenaline 4-0-

sulphate (product I)
2.10

3.1
250 MHz ^H n.m.r. spectrum of noradrenaline 3-0- sulphate (product II)
93

Standard curve for the estimation of dopamine 3- and 4-0-sulphates

105

H.p.l.c. chromatogram of dopamine £-sulphate

  • standards
  • 107

108
H.p.l.c. chromatogram of normal urine containing both dopamine 0-sulphates

H.p.l.c. chromatogram of urine after L-dopa administration, for estimation of dopamine 4-0-

  • sulphate content
  • 109

H.p.l.c. chromatogram of urine presented in Fig. 3.4, appropriately iiluted for estimation

  • of 3-0-sulphate content
  • •••
  • •••

110

120

122

124 126 128 130 132 134 143
H.p.l.c. chromatogram of authentic noradrenaline
••• brain homogenate
•••
••• ••• ••• •••
3- and 4-0-sulphates H.p.l.c. chromatogram of (rabbit 4) H.p.l.c. chromatogram of heart homogenate (rabbit 4)
•«• kidney homogenate
•••
H.p.l.c. chromatogram of (rabbit 4) H.p.l.c. chromatogram of (rabbit 4) spleen homogenate
H.p.l.c. chromatogram of liver homogenate (rabbit 4) H.p.l.c. chromatogram of small intestine homogenate (rabbit 4) H.p.l.c. chromatogram of small intestine homogenate following hydrolysis (rabbit 4) ... Radioenzymatic (PNMT) assay for the determination of free noradrenaline

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  • A Computational Tool for Pathway-Based Rational Drug Repositioning Supplementary Information

    A Computational Tool for Pathway-Based Rational Drug Repositioning Supplementary Information

    gene2drug: a Computational Tool for Pathway-based Rational Drug Repositioning Supplementary Information Francesco Napolitano1, Diego Carrella1, Barbara Mandriani1, Sandra Pisonero1, Diego Medina1, Nicola Brunetti-Pierri1,2, and Diego di Bernardo1,3 1Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli (NA), 80078, Italy. 2Department of Translational Medicine, Federico II University, 80131 Naples, Italy 3Department of Chemical, Materials and Industrial Production Engineering, University of Naples Federico II, 80125 Naples, Italy. List of Figures S1 Relation between PPI network-based and pathway based approaches. Given a therapeutic gene and the set of pathways it is annotated to according to the different databases, the other genes in the same pathways are topologically closer to it in the PPI network as compared to randomly chosen genes. The average shortest path from the selected gene to other pathway members is reported on the y axis for each database. 3 S2 Size of intersection between existent evidence scores in the STITCH database (subset matched against the Cmap database) as a percentage of the total number of evidences. Numbers on the diagonal represent how many times a drug-target evidence exists divided by the total number of reported pairs. A \combined score" always exist if one of the other evidences exist, thus \combined score" covers 100% of the pairs. Conversely, an \experimental" score is only present for 14% of the pairs. The \Text mining" evidence strongly drives the \combined score" covering 61% of all the known protein-target interactions in STITCH. 4 S3 Relative luminescence units (RLU) in Hepa1-6 cells transfected with a plasmid ex- pressing the luciferase gene under the control of the GPT promoter and incubated with various concentrations of fulvestrant.
  • Characterization and Regulation of the Resistance-Nodulation-Cell

    Characterization and Regulation of the Resistance-Nodulation-Cell

    Pletzer and Weingart BMC Microbiology 2014, 14:185 http://www.biomedcentral.com/1471-2180/14/185 RESEARCH ARTICLE Open Access Characterization and regulation of the Resistance-Nodulation-Cell Division-type multidrug efflux pumps MdtABC and MdtUVW from the fire blight pathogen Erwinia amylovora Daniel Pletzer and Helge Weingart* Abstract Background: The Gram-negative bacterium Erwinia amylovora is the causal agent of the devastating disease fire blight in rosaceous plants such as apple, pear, quince, raspberry, and cotoneaster. In order to survive and multiply in a host, microbes must be able to circumvent the toxic effects of antimicrobial plant compounds, such as flavonoids and tannins. E. amylovora uses multidrug efflux transporters that recognize and actively export toxic compounds out of the cells. Here, two heterotrimeric resistance-nodulation-cell division (RND)-type multidrug efflux pumps, MdtABC and MdtUVW, from E. amylovora were identified. These RND systems are unusual in that they contain two different RND proteins forming a functional pump. Results: To find the substrate specificities of the two efflux systems, we overexpressed the transporters in a hypersensitive mutant lacking the major RND pump AcrB. Both transporters mediated resistance to several flavonoids, fusidic acid and novobiocin. Additionally, MdtABC mediated resistance towards josamycin, bile salts and silver nitrate, and MdtUVW towards clotrimazole. The ability of the mdtABC- and mdtUVW-deficient mutants to multiply in apple rootstock was reduced. Quantitative RT-PCR analyses revealed that the expression of the transporter genes was induced during infection of apple rootstock. The polyphenolic plant compound tannin, as well as the heavy metal salt tungstate was found to induce the expression of mdtABC.
  • Prestwick Collection

    Prestwick Collection

    (-) -Levobunolol hydrochloride (-)-Adenosine 3',5'-cyclic monophosphate (-)-Cinchonidine (-)-Eseroline fumarate salt (-)-Isoproterenol hydrochloride (-)-MK 801 hydrogen maleate (-)-Quinpirole hydrochloride (+) -Levobunolol hydrochloride (+)-Isoproterenol (+)-bitartrate salt (+,-)-Octopamine hydrochloride (+,-)-Synephrine (±)-Nipecotic acid (1-[(4-Chlorophenyl)phenyl-methyl]-4-methylpiperazine) (cis-) Nanophine (d,l)-Tetrahydroberberine (R) -Naproxen sodium salt (R)-(+)-Atenolol (R)-Propranolol hydrochloride (S)-(-)-Atenolol (S)-(-)-Cycloserine (S)-propranolol hydrochloride 2-Aminobenzenesulfonamide 2-Chloropyrazine 3-Acetamidocoumarin 3-Acetylcoumarin 3-alpha-Hydroxy-5-beta-androstan-17-one 6-Furfurylaminopurine 6-Hydroxytropinone Acacetin Acebutolol hydrochloride Aceclofenac Acemetacin Acenocoumarol Acetaminophen Acetazolamide Acetohexamide Acetopromazine maleate salt Acetylsalicylsalicylic acid Aconitine Acyclovir Adamantamine fumarate Adenosine 5'-monophosphate monohydrate Adiphenine hydrochloride Adrenosterone Ajmalicine hydrochloride Ajmaline Albendazole Alclometasone dipropionate Alcuronium chloride Alexidine dihydrochloride Alfadolone acetate Alfaxalone Alfuzosin hydrochloride Allantoin alpha-Santonin Alprenolol hydrochloride Alprostadil Althiazide Altretamine Alverine citrate salt Ambroxol hydrochloride Amethopterin (R,S) Amidopyrine Amikacin hydrate Amiloride hydrochloride dihydrate Aminocaproic acid Aminohippuric acid Aminophylline Aminopurine, 6-benzyl Amiodarone hydrochloride Amiprilose hydrochloride Amitryptiline hydrochloride