Novel Benzindoloazecines and Dibenzazecines [Elektronische Ressource] : Synthesis and Affinities for the Dopamine Receptors / Dina Robaa. Gutachter: Jochen Lehmann ; Gerhard Scriba ; Peter Gmeiner

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• Publié par: friedrich-schiller-universitat_jena
• Publié le: 01 janvier 2011
• Nombre de lectures: 26
• Langue: English
• Poids de l'ouvrage: 7 Mo

Extrait

Novel Benzindoloazecines and
Dibenzazecines -
Synthesis and Affinities for the
Dopamine Receptors


Dissertation
zur Erlangen des akademischen Grades
Doctor rerum naturalium
(Dr. rer. nat.)

Vorgelegt dem Rat der Biologisch-Pharmazeutischen Fakultät
der Friedrich-Schiller-Universität Jena


von
Dina Robaa

geboren am 17. Oktober 1978 in Alexandria



















1. Gutachter: Prof. Dr. Jochen Lehmann, Jena
2. Gutachter: Prof. Dr. Gerhard Scriba, Jena
3. Gutachter: Prof. Dr. Peter Gmeiner, Erlangen


Tag der öffentlichen Verteidigung: 5. Mai 2011
I

Table of contents
1. Introduction ................................................................................................................... 1
1.1. Receptor structure ....................................................................................................... 3
1.2. Tissue distribution ............... 4
1.3. Signal transduction ............................................................... 6
1.4. Functions of the dopamine receptors and their therapeutic implications ............... 7
1.4.1. Control of locomotion and application in movement disorders ..................................... 7
1.4.2. Role in reward and reward-seeking behavior and clinical implication in
drug abuse and addictive disorders ............................................................................. 8
1.4.3. Role in psychosis and schizophrenia ......... ............................................................... 10
1.5. Dopamine receptor ligands ......................... 12
1.5.1. Phenylbenzazepines .........................................................................12
1.5.2. Tetrahydroisoquinoline derivatives ............................................................................. 14
1.5.2.1. 1-Benzyl/1-phenyl tetrahydroisoquinolines .............................................................. 14
1.5.2.2. Aporphines ..............................................................................................................15
1.5.2.3. Tetrahydroprotoberberines (THPBs) ....................................................................... 16
1.5.2.4. Dihydrexidine and dinapsoline derivatives 17
1.5.3. Indolobenzazecines and Dibenzazecines ................................................................... 18
2. Aim of this work ..........................................................................................................23
3. Manuscripts ........................................................................................27
Paper 1
Dopamine Receptor Ligands. Part 18: Modification of the Structural Skeleton of
Indolobenzazecine-Type Dopamine Receptor Antagonists .................................................. 28
Paper 2
Residues at the Indole-NH of LE300 Modulate Affinities and Selectivities for
Dopamine Receptors ...........................................................................................................29
Paper 3
Molecular Combination of the Dopamine and Serotonin Scaffolds Yields Novel
Antipsychotic Drug Candidates – Characterization by in vivo Experiments .......................... 30
Paper 4
Synthesis and Dopamine Receptor Affinities of Racemic and Enantiopure
Indolo[3,2-f][3]benzazecine Derivatives ............................................................................... 31
Paper 5
A Novel Nonphenolic Dibenzazecine Derivative with Nanomolar Affinities for
Dopamine Receptors ...........................................................................................................32
II Table of Contents


4. Unpublished results ...................................................................................................33
4.1. Trials to synthesize the [4,3-ef][2]benzazecine and indolo[4,3-de][2]-
benzazonine derivatives 3 and 4 .................33
4.2. LE300 substituted at the methylene bridge ...............................................................34
4.2.1. Substitution of LE300 with an ethyl group at the methylene bridge .............................34
4.2.2. Trials to synthesize an LE300 derivative bearing a methoxy group at the
methylene bridge .......................................................................................................35
4.2.3. Affinities for the dopamine receptors ...........36
4.3. 8-Substituted benzindoloazecines .............................................................................37
4.3.1. Racemized benzindoloazecines derived from D- and L-tryptophan ............................37
4.3.2. Enantiopure 8R- and 8S-methyl benzindoloazecine: Understanding
the reason behind the discrepancy in their affinities ....................................................40
4.4. Substitution of the alicyclic N with longer and functionalized side chains ............44
4.5. Synthetic procedures, spectral and analytical data .................................................47
5. Discussion ....................................................................................................................51
5.1. Synthesis of the different quinolizine derivatives as important
precursors for the target azecines .............................................................................53
5.2. Modulation of the annulation pattern of LE300 .........................................................55
5.3. Substitution of LE300 at different positions .............................................................57
5.3.1. N14-substituted LE300 derivatives .............................................................................57
5.3.2. LE300 bearing substituents between the aromatic rings.............................................58
5.3.3. LE300 substituted at position 8 ..................................................................................59
5.4. Methylenedioxydibenzazecine derivative ..................................................................62
5.5. Antipsychotic potential ...............................................................................................63
6. Conclusion ...................................................................................................................68
7. Zusammenfassung ......................................71
8. References ...................................................................................................................74
9. Appendix ............................................................................................82
List of abbreviations
Curriculum vitae
List of publications
Selbstständigkeitserklärung
Acknowledgement
1

1. Introduction
1It was in the late 1950’s after the discovery of dopamine’s wide distribution in the brain , that
dopamine’s function as a neurotransmitter and not as previously believed a mere precursor
in the biosynthesis of epinephrine and norepinephrine was first recognized. Interest in
dopamine grew after subsequent findings of its role in the pathogenesis of Parkinson’s
2 3disease and schizophrenia .
Today, dopamine is known as a major neurotransmitter in the CNS, where it controls a
myriad of physiological functions, including locomotion, behavior, emotion, cognition, learning
and motivation in addition to endocrine secretion. Dysfunctions of the dopaminergic system
have been linked with several neurological and psychiatric disorders in addition to
4 5Parkinson’s disease and schizophrenia. These include depression , Tourette’s syndrome ,
6 7attention-deficit hyperactivity disorder (ADHD) as well as drug and alcohol dependence .
Modulation of the dopamine transmission by targeting either the dopamine receptors or its
transporter is hence a main strategy or central focus of research in the treatment of these
disorders.
The search for new ligands acting at the different dopamine receptors is for several reasons
still of major importance.
The lack of subtype selective ligands, especially those which are able to differentiate
between D and D receptors, has been a major impediment in the way of clarifying the 1 5
physiological role of the individual receptors. Most of the studies concerning the functions of
the dopamine receptors have been carried out using genetically modified mice. Although
valuable information has been obtained, the inconsistency of the results and the limitations of
this strategy have proven that subtype selective ligands are indispensible as pharmacological
tools to study both the physiological role and the possible clinical implication of the different
dopamine receptor subtypes.
Subtype selective ligands would also be of major value in exploring the binding site of the
dopamine receptors. They can help determine the structural, spatial and stereochemical
features necessary for distinguishing between the different receptor subtypes. This will in
turn help get further insights into the binding site of the receptor subtypes.
Dopamine receptor ligands have long been used in the therapy of neurological diseases, in
particular of Parkinson’s disease (agonists) and schizophrenia (antagonists).