Donald F. Weaver

The Development of New Therapeutics for Alzheimer's Disease

Existing treatments for Alzheimers disease (AD) fail to address the underlying pathology of the disease; they merely provide short‐lived symptomatic relief. Consequently, the progression of AD is unrelenting, leading to a continual decrease in cognitive abilities. Recent advances in understanding the genetic factors that predispose to AD, as well as in biomarker development, have brought with them the promise of earlier and more reliable diagnosis of this disease. As improvements continue to be made in these areas, the shortcomings of current AD treatments appear all the more acute because opportunities for early intervention are hindered by a lack of “curative” or even disease‐modifying drugs. This State of the Art report reviews existing AD therapeutics and highlights recent progress made in the design and development of drugs that are aimed at disrupting AD disease progression by inhibition of the protein misfolding of β‐amyloid (Aβ) into neurotoxic oligomeric aggregates.

β-Alanine as a small molecule neurotransmitter

This review discusses the role of beta-alanine as a neurotransmitter. Beta-alanine is structurally intermediate between alpha-amino acid (glycine, glutamate) and gamma-amino acid (GABA) neurotransmitters. In general, beta-alanine satisfies a number of the prerequisite classical criteria for being a neurotransmitter: beta-alanine occurs naturally in the CNS, is released by electrical stimulation through a Ca(2+) dependent process, has binding sites, and inhibits neuronal excitability. beta-Alanine has 5 recognized receptor sites: glycine co-agonist site on the NMDA complex (strychnine-insensitive); glycine receptor site (strychnine sensitive); GABA-A receptor; GABA-C receptor; and blockade of GAT protein-mediated glial GABA uptake. Although beta-alanine binding has been identified throughout the hippocampus, limbic structures, and neocortex, unique beta-alaninergic neurons with no GABAergic properties remain unidentified, and it is impossible to discriminate between beta-alaninergic and GABAergic properties in the CNS. Nevertheless, a variety of data suggest that beta-alanine should be considered as a small molecule neurotransmitter and should join the ranks of the other amino acid neurotransmitters. These realizations open the door for a more comprehensive evaluation of beta-alanines neurochemistry and for its exploitation as a platform for drug design.

Improving the clinical assessment of consciousness with advances in electrophysiological and neuroimaging techniques

In clinical neurology, a comprehensive understanding of consciousness has been regarded as an abstract concept - best left to philosophers. However, times are changing and the need to clinically assess consciousness is increasingly becoming a real-world, practical challenge. Current methods for evaluating altered levels of consciousness are highly reliant on either behavioural measures or anatomical imaging. While these methods have some utility, estimates of misdiagnosis are worrisome (as high as 43%) - clearly this is a major clinical problem. The solution must involve objective, physiologically based measures that do not rely on behaviour. This paper reviews recent advances in physiologically based measures that enable better evaluation of consciousness states (coma, vegetative state, minimally conscious state, and locked in syndrome). Based on the evidence to-date, electroencephalographic and neuroimaging based assessments of consciousness provide valuable information for evaluation of residual function, formation of differential diagnoses, and estimation of prognosis.

Development of quantitative structure-activity relationships and classification models for anticonvulsant activity of hydantoin analogues.

Classification and QSAR analysis was performed on a large set of hydantoin derivatives with measured anticonvulsant activity in mice and rats. The classification set comprised 287 hydantoins having maximal electroshock (MES) activity expressed in qualitative form. A subset of 94 hydantoins with MES ED(50) values was used for QSAR analysis. Numerical descriptors were generated to encode topological, geometric/structural, electronic, and thermodynamic properties of molecules. Analyses were performed with training and test sets of diverse compounds selected using their representation in a principal component space. Cell- and distance metric-based selection methods were employed in this process. For QSAR, a genetic algorithm (GA) was used for selecting subsets of 5-9 descriptors that minimize the rms error on the training sets. The most predictive models have rms errors of 0.86 (r(2) = 0.64) and 0.73 (r(2) = 0.75) ln(1/ED(50)) units on the cell- and distance metric-derived test sets, respectively, and showed convergence in the selected descriptors. Classification models were developed using recursive partitioning (RP) and spline-fitting with a GA (SFGA), a novel method we have implemented. The most predictive RP and SFGA models have classification rates of 75% and 80% on the test sets; both methods produced models with similar discriminating features. For QSAR and classification, consensus schemes gave improved predictive accuracy.

The “promiscuous drug concept” with applications to Alzheimer’s disease

Arguably, Alzheimers disease (AD) is a multifactorial syndrome, rather than single disease, arising from a complex array of neurochemical factors. Numerous studies on the molecular pathogenesis of AD implicate a diversity of factors ranging from neurotoxic peptides (β‐amyloid) to inflammatory processes (interleukins), but all culminating in a common neuropathology. This diversity of molecular causation is an impediment to the design of effective therapies for AD. To address this design problem, we sought to identify a single, common motif (a “common receptor”) shared by multiple structurally and functionally diverse proteins implicated in AD. This search revealed the presence of a common BBXB peptide motif and upon refinement, an AXBBXB motif; these regions can be exploited for the design of a “promiscuous drug” that exploits a “one‐drug‐multiple‐receptors” therapeutic strategy for AD.

Pharmacoresistant epilepsy: Unmet needs in solving the puzzle(s)

Pharmacoresistant epilepsy is a significant medical problem. The 2nd Halifax International Epilepsy Conference & Retreat identified crucial needs, which if successfully addressed, will aid in paving the way to improved lives for people with pharmacoresistant epilepsy. These are needs: (1) for an evidence‐based and dynamic definition of pharmacoresistant epilepsy; (2) for a comprehensive description of the natural history of pharmacoresistant epilepsy; (3) for a comprehensive description of the complications and comorbidities of pharmacoresistant epilepsy; (4) for a rigorous delineation of the epidemiology and socioeconomic impact of pharmacoresistant epilepsy; (5) for clinically meaningful diagnostic and prognostic physiologically based electroencephalography (EEG) biomarkers; (6) for clinically meaningful diagnostic and prognostic anatomically based (MRI Imaging) biomarkers; (7) for biomolecular/biochemical mechanistic understanding of etiopathogenesis for pharmacoresistant epilepsy; (8) for representative animal models of pharmacoresistant epilepsy; (9) for new and effective drugs or other novel treatments for pharmacoresistant epilepsy; and (10) to promote continuing research and research funding targeting pharmacoresistant epilepsy.

Anaesthetic binding sites for etomidate and propofol on a GABAA receptor model

Investigating the molecular basis of general anaesthetic activity at the GABA(A) ligand-gated ion channel is challenging due to the wide structural diversity among known general anaesthetics, and the lack of an experimental structure for the GABA(A) protein. In this molecular modelling study, two distinct binding cavities were identified within the beta(2) subunit of the transmembrane domain in a molecular model of the GABA(A) protein. The first, located near the centre of the alpha-helical bundle, contains Asn265 (TM2), which is essential for modulation by etomidate. The second, located near the TM1, TM3 and TM4 segments close to the membrane-extracellular interface, is capped by Met286 (TM3), a residue thought to be involved in the propofol binding site. Potential interactions of etomidate and propofol with other side-chains were also identified.

N-, α-, and β-Substituted 3-Aminopropionic acids: design, syntheses and antiseizure activities

Abstract A treatment for epilepsy is proposed based on analogues of 3-aminopropionic acid (β-alanine), a putative neurotransmitter in the central nervous system (CNS). A model three point pharmacophore was proposed based on modelling data obtained from the study of antagonists for both the glial γ -aminobutyric acid (GABA)-uptake site and the glycine co-agonist site of N -methyl- d -aspartate (NMDA) receptor. Three series of 3-aminopropionic acids containing, N -, α-, and β-substituents, were designed and synthesized to probe the position and the size of a lipophilic binding pocket within the proposed pharmacophore. These analogues were tested in vivo for both their antiseizure activities and their neurologic toxicities. Among the fourteen novel 3-aminopropionic acids synthesized, eight were found to have promising antiseizure activity. This study shows that substitution on the N-terminus confers the greatest antiseizure activity, particularly against pilocarpine-induced seizures.

Functionalized amido ketones: new anticonvulsant agents.

We have reported that functionalized amino acids (FAA) are potent anticonvulsants. Replacing the N-terminal amide group in FAA with phenethyl, styryl, and phenylethynyl units provided a series of functionalized amido ketones (FAK). We show that select FAK exhibit significant anticonvulsant activities thereby providing information about the structural requirements for FAA and FAK bioactivity.

Towards Brain First-Aid: A Diagnostic Device for Conscious Awareness

When the brain is damaged, evaluating an individuals level of awareness can be a major diagnostic challenge (Is he or she in there?). Existing tests typically rely on behavioral indicators, which are incorrect in as many as one out of every two cases. The current paper presents a diagnostic device that addresses this problem. The technology circumvents behavioral limitations through noninvasive brain wave measurements (electroencephalography, or EEG). Unlike traditional EEG, the device is designed for point-of-care use by incorporating a portable, user-friendly, and stable design. It uses a novel software algorithm that automates subject stimulation, data acquisition/analysis, and the reporting of results. The test provides indicators for five identifiable levels of neural processing: sensation, perception, attention, memory, and language. The results are provided as rapidly obtained diagnostic, reliability, validity, and prognostic scores. The device can be applied to a wide variety of patients across a host of different environments. The technology is designed to be wireless-enabled for remote monitoring and assessment capabilities. In essence, the device is developed to scan for conscious awareness in order to optimize subsequent patient care.