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

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 8

modulators as a treatment for schizophrenia

1.2.3 Therapeutic rationale for NMDA receptor positive allosteric 12

modulators as cognitive enhancers

1.2.4 Therapeutic rationale for NMDA receptor positive allosteric 14

modulators as a treatment for anxiety disorders

1.2.2 Classes of NMDA receptor modulators 15

1.2.6 Mechanism and action of tetrahydroisoquinoline class of 20

compounds known as CIQ

1.2.7 Overview of previous structure activity relationship for 25

tetrahydroisoquinoline class

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 94


2.2.2 Endogenous compounds for GluN2B-containing NMDA 95


2.2.3 Photocrosslinking 96

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

class from CIQ

2.3 Synthesis of tetrahydroisoquinoline-containing compounds with 104

GluN2B potentiator activity

2.3.1 Synthetic routes towards oxygen-containing racemic 104

tetrahydroisoquinoline-containing compounds

2.3.2 Synthetic routes towards nitrogen-containing racemic 112

tetrahydroisoquinoline-containing compounds

2.3.3 Steps to cyclize the tetrahydroisoquinoline core and installation 114

of the A-ring

2.3.4 Synthesis of enantiomers of 1180-55 and 1180-163122

2.3.5 Separation of 1180-264, 1180-87, 1180-103, and 1180-92 129

enantiomers via the chiral AD-H prep column

2.3.6 Synthesis of compounds for initial photoaffinity labeling 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 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 161

amide-containing compounds

2.4.8 Evaluation of 1180-55 and 1180-163 enantiomers to discern 164

stereoselectivity of isopropoxy-containing compounds

2.4.9 Evaluation of 1180-87 and 1180-154 enantiomers with the goal 165

of developing a GluN2B-selective compound

2.4.10 Evaluation of 1180-92, 1180-103, and 1180-168 enantiomers with 167

the goal of developing a GluN2B/GluN2C-selective compound

2.4.11 Relating the evaluation of enantiomers to the structural 171

determinants of the 1180-55 and CIQ tetrahydroisoquinoline classes

2.4.12 Initial evaluation of compounds for photoaffinity labeling 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 330

NMDA receptors

3.2 CIQ and 1180-55 are divergent regarding SAR 331

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

for potentiation

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