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UNIVERSIDAD COMPLUTENSE DE MADRID FACULTAD DE FARMACIA Departamento de Química Farmacéutica TESIS DOCTORAL Bioisosterism and conformational restriction: ligand- based design in the development of nicotinic ligands and melatonin analogues with neurogenic properties MEMORIA PARA OPTAR AL GRADO DE DOCTOR PRESENTADA POR Mario de la Fuente Revenga Directora María Isabel Rodríguez Franco Madrid, 2014 ©Mario de la Fuente Revenga, 2014 BIOISOSTERISMO Y RESTRICCIÓN CONFORMACIONAL: DISEÑO BASADO EN EL LIGANDO APLICADO AL ESTUDIO DE LA SELECTIVIDAD EN RECEPTORES NICOTÍNICOS Y AL DESARROLLO DE ANÁLOGOS DE MELATONINA CON PROPIEDADES NEUROGÉNICAS PhD thesis Mario de la Fuente Revenga IQM-CSIC Madrid, 2014 Universidad Complutense de Madrid Facultad de Farmacia Departamento de Química Farmacéutica Bioisosterism and conformational restriction: Ligand-based design in the development of nicotinic ligands and melatonin analogues with neurogenic properties PhD student Mario de la Fuente Revenga Supervisor María Isabel Rodríguez Franco, PhD. Research Scientist. Instituto de Química Médica, Consejo Superior de Investigaciones Científicas (IQM, CSIC) C/Juan de la Cierva 3, 28006. Madrid Spain Faculty of Health and Medical Sciences, University of Copenhagen Scientific stay (April – October 2011, March – June 2012) Supervisor Bente Frølund, PhD. Associate Professor. Department of Drug Design and Pharmacology Faculty of Health and Medical Sciences Medicinal Chemistry Research, University of Copenhagen Jagtvej 162, 2100 Copenhagen Ø Denmark INDEX Prologue ……………………………………………………………………………………………….... 1 Chapter 1. Design, synthesis and pharmacological characterization of novel melatonin analogues based on the bioisosteric replacement of its N-acetyl moiety for azoles and retroamides……………………………………... 3 Introduction…………………………………………………………....................................................... 3 Approach…………………………………………………….................................................. 9 Chemistry……………………………………………………………........................................................ 10 Synthesis of retroamides and oxazoles ………………………………... 10 Synthesis of 1,2,4- and 1,3,4-oxadiazoles ……………………………... 12 Synthesis of 4-alkyl-1,2,4-triazol-5-(thio)ones and 2- amino-1,3,4-thiadiazol………………………………………………………………. 14 Synthesis of 1,3,4-oxadiazol-2-(thio)ones …………………………….. 17 NMR studies on the tautomerism of hydrogen-bearing azoles …………………………………………………………………………………………… 17 Pharmacology…………………………………………………………………………………………... 22 Radioligand binding studies on melatonin receptors MT1 and MT2 ……………………………………………………………………………………….. 22 i Functional studies on melatonin receptors MT1 and MT2... 25 Thermodynamic solubility studies…………………………………………………… 27 Discussion………………………………………………………………………………………………… 29 Conclusions……………………………………………………………………………………………… 36 Experimental section……………………………………………………………………………... 38 Bibliography……………………………………………………………………………………………. 58 Chapter 2. Neurogenesis studies on melatonin analogues......................... 67 Introduction …………………………………………………………………………………………….. 67 Results……………………………………………………………………………………………………….. 69 In vitro neural differentiation and maturation in the presence of different melatonin analogues …………………………. 69 In vivo neural differentiation and maturation after chronic treatment with 1.21……………………………………………………... 79 Discussion ……………………………………………………………………………………. 82 Conclusions ………………………………………………………………………………… 88 Experimental section ……………………………………………………………….. 90 Bibliography ………………………………………………………………………………. 94 Chapter 3. Pinoline pharmacological characterization and development of rigid melatonin-pinoline hybrids with neurogenic potential ………………………………………………………………………………………………………………… 99 Introduction ………………………………………………………………………………. 99 Approach……………………………………………………………………….. 103 Chemistry …………………………………………………………………………………… 105 Pharmacology…………………………………………………………………………….. 108 ii Serotonin receptors and transporter ……………………….. 108 Inhibition of monoamine-oxidase A and B ……………. 111 Affinity and intrinsic activity at melatonin receptors …………..…………..…………..…………..…………..…………….. 112 Blood-brain barrier permeability …………..…………………. 113 In vitro antioxidant potential …………………………………….. 113 Neurogenesis studies in vitro …………..…………..……………. 115 Discussion …………..…………..…………..…………..…………..…………. 121 Conclusions …………..…………..…………..…………..…………..……… 130 Experimental section ………..…………..…………..…………………. 132 Bibliography …………..…………..…………..…………..…………..…….. 140 Chapter 4. Conformationally restrained carbamoylcholine analogues and bioisosteres. Design, synthesis and pharmacology at nicotinic acetylcholine receptors (nAChRs) …………..…………..…………..…………..…………..……… 149 Introduction …………..…………..…………..…………..…………..…………..…………..………… 149 Approach …………..…………..…………..…………..…………..…………..……………. 154 Chemistry …………..…………..…………..…………..…………..…………..…………..…………….. 156 Synthesis of restricted analogues of DMABC (4.1) …………… 156 Synthesis of oxadiazole-containing DMABC (4.1) analogues …………..…………..…………..…………..…………..…………..……………. 163 Pharmacology …………..…………..…………..…………..…………..…………..…………..…….. 164 Binding at recombinant nAChRs …………..…………..…………..………. 164 Functional characterization at recombinant nAChRs ………. 167 Molecular modelling. Docking studies………….. …………..…………..……….. 169 Conclusions …………..…………..…………..…………..…………..…………..…………..………… 173 iii Experimental section …………..…………..…………..…………..…………..…………..……. 174 Bibliography …………..…………..…………..…………..…………..…………..…………..……… 201 Epilogue …………..…………..…………..…………..…………..…………..…………..…………..…………..…… 207 Concluding remarks…………..…………..…………..…………..…………..…………..……… 207 Bibliograpy…………..…………..…………..…………..…………..…………..…………..…………... 217 Abstract ………………………………………………………………………………………………………………….. 219 Resumen ………………………………………………………………………………………………………………... 225 iv Prologue This thesis consists of four different chapters. Each chapter is written in a full- paper style. When data from a previous chapter has been used, it appears mentioned in the text. All chapters share and differ in the approaches and the systems to which they are addressed. Two different traditional medicinal chemistry approaches, bioisosterism and conformational restriction, have provided novel ligands for two different systems, melatoninergic and cholinergic system. Preliminar studies on their pharmacological mechanism and potential as novel tools for neurodegenerative diseases have been initiated for some of them. Since each chapter contains its own introduction, specific approach, methodologies, results, discussion and conclusions, in the epilogue of this thesis work general concluding remarks are made in order to provide a general overview of the whole work. 1 2 Chapter 1 Design, synthesis and pharmacological characterization of novel melatonin analogues based on the bioisosteric replacement of its N-acetyl moiety for azoles and retroamides Introduction Melatonin receptors MT1 and MT2 lack a crystalized structure that would permit the characterization of the tertiary structure of these G protein- coupled receptors (GPCRs) and of the pattern of interactions undertaken with their ligands. The structural knowledge gained along the years emerges from homology models based on other crystalized transmembrane-receptors structure and site directed-mutagenesis studies. Unlike other GPCRs that lack a crystal structure, melatonergic receptors MT1 and MT2 have some additional limitations: lack of a reliable template to build the homologous constructs, and the elusive ligand-receptor interactions1,2. Rhodopsin and more recently aminergic GPCRs are the most common templates used in melatonin receptor homology modeling3. However, sequence alignments are rather poor, 3 providing structural models whose reliability has still to be proven. The low identity of the sequences increases the degree of speculation, and the poor usefulness of these models for drug design purposes4. Additionally, the nature of the endogenous ligand limits the identification of important ligand-receptor interactions. Melatonin lacks a charged group at physiological pH that would facilitate the identification of ionic interactions, like in the case of its parent amino-compound, the neurotransmitter serotonin1. As abovementioned, mutagenesis studies have provided some insights into the putative binding 5 mode of melatonin . In the case of MT1 receptor three amino acids have been identified as key contacts for ligand binding Ser110, Ser114 and His1956,7. In the case of MT2 several amino acids were identified as important for molecular recognition: Asn175, Val204, Asn268, Leu272, Ala275, Val291, Leu295, Tyr298 8,9 and Tyr188 . In the case of MT2, consistent with the physicochemical properties of the natural ligand, the number and the lipophilicity of the amino acids involved in melatonin binding suggest the presence of a network of contacts characterized by the lack of strong polar interactions. This structural feature complicates the identification of an unambiguous binding pose for melatonin or synthetic analogues. Therefore, till now, structure-based design has not been a suitable approach for the design of novel melatonin ligands. Ligand-based drug design has been widely exploited and has provided two marketed drugs: agomelatine (Valdoxan®) for major depression and ramelteon (Rozerem®) for sleeping disorders, and other ligands are in development stages10. Subtle and major changes on melatonin structure have provided a plethora of ligands, in many cases able to beat the picomolar affinity of melatonin for its receptors, and several pharmacophoric models have been proposed4,11,12. Among the different pharmacophores
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