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 It was in the late 1950’s after the discovery of dopamine’s wide distribution in the brain1, 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 disease2 and schizophrenia3. 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 Parkinson’s disease and schizophrenia. These include depression4, Tourette’s syndrome5, attention-deficit hyperactivity disorder (ADHD)6 as well as drug and alcohol dependence7. 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 D1 and D5 receptors, has been a major impediment in the way of clarifying the 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). Despite the availability of numerous dopamine antagonists, used in the therapy of schizophrenia,