The Design, Synthesis, and Biological Evaluation of Subunit-selective N-Methyl-D-Aspartate Receptor Potentiators Open Access

Strong, Katie Lynne (2015)

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N-methyl-d-aspartate (NMDA) receptors are ionotropic glutamate receptors that mediate a slow, Ca2+-permeable component of excitatory synaptic transmission. These receptors are important for a number of normal neurophysiological processes, and the dysfunction of the NMDA receptor has been indicated in a variety of neurological disorders. For this reason, identification of new pharmacological and therapeutic probes that selectively potentiate specific subunits of this receptor could be of therapeutic relevance. One such subunit-selective potentiator is the tetrahydroisoquinoline compound known as CIQ, which selectivity potentiates GluN2C- and GluN2D-containing NMDA receptors. Chapter One of this thesis discusses the continued structure activity relationship (SAR) around CIQ in an effort to explore important regions of the molecule and to increase potency. The most active analogs tested in Chapter One have EC50 values at the GluN2C and GluN2D subunits of 0.26 μM and 0.40 μM, respectively. Chapter Two of this thesis discusses how a specific modification on CIQ yielded a compound, referred to as 1180-55, that not only potentiated the GluN2C and GluN2D subunits, but also the GluN2B. An SAR around 1180-55 has led to potentiators that have varying degrees of subunit selectivity, including one compound that is selective for the GluN2B subunit. The best-in-class pan-potentiators have EC50 values at all three subunits of approximately 0.30 μM. Separation of the enantiomers for a potent potentiator of the GluN2B-, GluN2C-, and GluN2D-containing receptors revealed that the S-(-) enantiomer is active at GluN2B, GluN2C, and GluN2D subunits, while the R-(+) enantiomer is GluN2C and GluN2D subunit selective. By conducting an SAR and studying the stereoselectivity of this class of 1180-55 compounds, it has been shown that the 1180-55 scaffold can be tuned to target different GluN2 subunits of the NMDA receptor. This tetrahydroisoquinoline class of compounds is no longer limited to the activation of only GluN2C and GluN2D subunits.

Table of Contents

Chapter 1: The Continued Design, Synthesis, and Biological Evaluation of a GluN2C/D-Selective NMDA Receptor Class of Tetrahydroisoquinoline Potentiators

Chapter 1

1.1 Statement of purpose 1

1.2 Introduction and background 2

1.2.1 NMDA structure, function and localization 2

1.2.2 Therapeutic rationale for NMDA receptor positive allosteric modulators as a treatment for schizophrenia 8

1.2.3 Therapeutic rationale for NMDA receptor positive allosteric modulators as cognitive enhancers 12

1.2.4 Therapeutic rationale for NMDA receptor positive allosteric modulators as a treatment for anxiety disorders 14

1.2.2 Classes of NMDA receptor modulators 15

1.2.6 Mechanism and action of tetrahydroisoquinoline class of compounds known as CIQ 20

1.2.7 Overview of previous structure activity relationship for tetrahydroisoquinoline class 25

1.3 Synthesis of and rationale for GluN2C/D-selective positive modulators 27

1.3.1 Shortened linker between core and B-ring 27

1.3.2 Nitrogen functionality on B-ring 28

1.3.3 Compounds with thioamide linker between core and A-ring 32

1.3.4 Modifications to the C-ring 33

1.3.5 Separation of enantiomers for select analogs 36

1.4 Results and Discussion 37

1.4.1 Shortened Linker between core and B-ring 37

1.4.2 Nitrogen functionality on B-ring 38

1.4.3 Compounds with thioamide linker between core and A-ring 39

1.4.4 Modifications to the C-ring 40

1.4.5 Separation of enantiomers for select analogs 42

1.5 Conclusions 43

1.6 Experimental details 44

1.6.1 Chemistry experimental procedures 44

1.6.2 In vitro analysis of 1180 series analogs 81

Chapter 2: The Structure Activity Relationship (SAR) of Tetrahydroisoquinoline Potentiators can be tuned to selectively target GluN2B-containing NMDA Receptors

Chapter 2

2.1 Statement of purpose 93

2.2 Introduction and background 94

2.2.1 Therapeutic rationale for GluN2B-selective NMDA positive modulators 94

2.2.2 Endogenous compounds for GluN2B-containing NMDA receptors 95

2.2.3 Photocrosslinking 96

2.2.4 The identification of 1180-55 and its emergence as a distinct class from CIQ 99

2.3 Synthesis of tetrahydroisoquinoline-containing compounds with GluN2B potentiator activity 104

2.3.1 Synthetic routes towards oxygen-containing racemic tetrahydroisoquinoline-containing compounds 104

2.3.2 Synthetic routes towards nitrogen-containing racemic tetrahydroisoquinoline-containing compounds 112

2.3.3 Steps to cyclize the tetrahydroisoquinoline core and installation of the A-ring 114

2.3.4 Synthesis of enantiomers of 1180-55 and 1180-163 122

2.3.5 Separation of 1180-264, 1180-87, 1180-103, and 1180-92 enantiomers via the chiral AD-H prep column 129

2.3.6 Synthesis of compounds for initial photoaffinity labeling experiments 131

2.4 Results and discussion 132

2.4.1 The effect of oxygen-containing functionality on the C-ring 133

2.4.2 The effect of nitrogen-containing functionality on the C-ring 136

2.4.3 The effect of A-ring modifications 139

2.4.4 Optimization of C-ring when A-ring and B-rings are held constant 144

2.4.5 Optimization of B-ring modifications 146

2.4.6 Optimization of linker between core and A-ring 150

2.4.7 Modeling the lowest energy conformations of thioamide- and amide-containing compounds 161

2.4.8 Evaluation of 1180-55 and 1180-163 enantiomers to discern stereoselectivity of isopropoxy-containing compounds 164

2.4.9 Evaluation of 1180-87 and 1180-154 enantiomers with the goal of developing a GluN2B-selective compound 165

2.4.10 Evaluation of 1180-92, 1180-103, and 1180-168 enantiomers with the goal of developing a GluN2B/GluN2C-selective compound 167

2.4.11 Relating the evaluation of enantiomers to the structural determinants of the 1180-55 and CIQ tetrahydroisoquinoline classes 171

2.4.12 Initial evaluation of compounds for photoaffinity labeling experiments 174

2.5 Conclusions 177

2.6 Experimental details 182

2.6.1 Chemistry experimental procedures 182

2.6.2 Computational analysis 316

2.6.3 Crystal structure data and experimental 316

2.6.4 In vitro analysis of 1180-55 series analogs 324

Chapter 3: CIQ and 1180-55 represent divergent class of compounds in terms of SAR, pharmacology, and molecular determinants for potentiation.

Chapter 3

3.1 The significance of a modulator for GluN2B-containing NMDA receptors 330

3.2 CIQ and 1180-55 are divergent regarding SAR 331

3.3 CIQ and 1180-55 are divergent regarding structural determinants for potentiation 333

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