Abstract by Christoffer Mentz

Part A: Design and Synthesis of Tool Compounds to Probe the “Open Conformation” Ligand Binding Domain of Glutamate Delta1 and 2 Receptors (δ1 & δ2).

The delta receptors (GluD1 and GluD2) were classified as members of the ionotropic glutamate receptor (iGluR) family due to their significant sequence similarity to the other iGluR subfamilies. Mutations in the GluD2 gene (GRID2) have been associated with different brain disorders including speech and cognitive development delay. Furthermore, mutation in GluD1 gene (GRID1) have been associated with autism, schizophrenia, bipolar disorders and speech and motor-skill developmental disorders.

No endogenous ligand was found to bind the GluD receptors until recently, where a study claimed that the GluD receptors are functional D-serine and glycine-gated ion channels. Despite this, D-serine is unable to activate ion channel currents on the wild-type delta receptors expressed in Xenopus oocytes. The GluD2 Lurcher mutant (GluD2^LC) leads to spontaneous channel activity which can be inhibited by ligands. Measurements of the current inhibition, by ligands, are hypothesized to be a method of assessing their potency towards GluD2. 

D-serine, has been found to have a relative potency at the GluD2^LC expressed in Xenopus oocytes of EC₅₀ = 182 µM. But with D-serine having high selectivity at the NMDA receptor subtype, GluN1, selective compounds still remains to be found. This is due to the GluD2-LBD similarity to that of the GluN1-LBD.

The NMDA receptor antagonist 7-Chlorokynurenic acid (7-CKA) has been found to bind GluD2^LC with an EC⁵⁰ value of 312 µM. By evaluation of the crystal structure containing 7-CKA, it was observed to have a different closing conformation of 19,5°, relative to D-serine at 0°, leading to the speculation that 7-CKA is a potential antagonist at GluD2.

In this thesis, using computational techniques and synthetic chemistry, ligands for both GluD1 and GluD2 were designed and synthesized with some ligands exhibiting pharmacological profiles of up to 3-4-fold increases in efficacy at 200 µM conc. relative to that of 7-CKA at the same concentration.

Part B: Unveiling the Mechanism Governing the Transformation of α-Saturated Ketones to 3,3-Dibromo-2-propen-1-ols.

Manipulation and transformations of functional groups are central to organic synthesis. These interconversions are often used to mask a functionality for subsequent conversion into its target functionality, or to introduce transient groups solely to construct the requisite carbon skeleton in target-oriented synthesis. Chemical transformations are fundamental in materials and medicinal chemistry, serving as the primary tools to access target molecules efficiently and economically, thus, discovery of new reactions expands the synthetic toolbox in these fields, to advance downstream research.

Recent work in the Bunch group has led to the discovery of a new chemical transformation of α-saturated ketones to densely functionalized 3,3-dibromo-2-propen-1-ols. Prior optimization efforts have established optimal conditions using Lithium hexamethyldisilazide (LiHMDS) and bromoform in tetrahydrofuran (THF) at -78 and then -20 ^◦C, yielding up to 90% with a variety of substrates including pyridines, anilines, and substituted aryl ketones. However, besides optimal reaction conditions, the scope and the underlying mechanism of the transformation remain elusive.

This thesis investigates the mechanism underlying the conversion of α-saturated ketones to 3,3-dibromo-2-propen-1-ols through systematic organic synthesis of putative intermediates, reaction monitoring via nuclear magnetic resonance (NMR) and mass spectrometry (MS), and targeted variations in specific reaction conditions and order of addition.

Key findings during these studies elucidates the dual-role of LiHMDS (relative to the ineffective Lithium diisopropylamide, LDA) involved in early and late stage of the reaction mechanism which ultimately led to a revised mechanism proposal supported by experimental evidence. Furthermore, an elusive side-product was isolated. And finally, the utility of the dibromoalkene scaffold is expanded upon through conversion, using previously known literature chemistry.