A5004341044- Receptor Mechanisms and Signaling
- Neuroscience and Neuropharmacology Research
- Pharmacological Receptor Mechanisms and Effects
- Ion channel regulation and function
- Nicotinic Acetylcholine Receptors Study
- Neuropeptides and Animal Physiology
- Chemical Synthesis and Analysis
- Computational Drug Discovery Methods
- Phosphodiesterase function and regulation
- Synthesis and Biological Evaluation
- X-ray Diffraction in Crystallography
- Superconducting Materials and Applications
- Neurotransmitter Receptor Influence on Behavior
- Medical Imaging Techniques and Applications
- Analytical Chemistry and Chromatography
- Crystallization and Solubility Studies
- Chemical Synthesis and Reactions
- Inorganic and Organometallic Chemistry
- Nitric Oxide and Endothelin Effects
- Lanthanide and Transition Metal Complexes
- Viral Infectious Diseases and Gene Expression in Insects
- Click Chemistry and Applications
- Pharmacogenetics and Drug Metabolism
- Synthesis of β-Lactam Compounds
- Cardiac electrophysiology and arrhythmias
Vanderbilt University
2014-2025
Center for Discovery
2025
University of Delaware
2023
Vanderbilt University Medical Center
2010-2021
Center for Neurosciences
2017
Institute of Pharmacology
2014
Duke University
2013
United States Department of Veterans Affairs
2009-2013
Monash University
2013
Janssen (Belgium)
2013
Recent studies suggest that subtype-selective activators of M 1 /M 4 muscarinic acetylcholine receptors (mAChRs) may offer a novel approach for the treatment psychotic symptoms associated with schizophrenia and Alzheimer's disease. Previously developed agonists have provided clinical data in support this hypothesis, but failed development because lack true subtype specificity adverse effects activation other mAChR subtypes. We now report characterization highly selective agonist receptor no...
M 1 muscarinic acetylcholine receptors (mAChRs) may represent a viable target for treatment of disorders involving impaired cognitive function. However, major limitation to testing this hypothesis has been lack highly selective ligands individual mAChR subtypes. We now report the rigorous molecular characterization novel compound, benzylquinolone carboxylic acid (BQCA), which acts as potent, positive allosteric modulator (PAM) rat receptor. This compound does not directly activate receptor,...
Previous clinical and animal studies suggest that selective activators of M<sub>1</sub> and/or M<sub>4</sub> muscarinic acetylcholine receptors (mAChRs) have potential as novel therapeutic agents for treatment schizophrenia Alzheimer9s disease. However, highly centrally penetrant either or not been available, making it impossible to determine the in vivo effects activation these receptors. We previously identified VU10010 [3-amino-<i>N</i>-(4-chlorobenzyl)-4,...
Activators of M<sub>1</sub> muscarinic acetylcholine receptors (mAChRs) may provide novel treatments for schizophrenia and Alzheimer9s disease. Unfortunately, the development M<sub>1</sub>-active compounds has resulted in nonselective activation highly related M<sub>2</sub> to M<sub>5</sub> mAChR subtypes, which results dose-limiting side effects. Using a functional screening approach, we identified several ligands that potentiated agonist with low micromolar potencies induced 5-fold or...
Positive allosteric modulators (PAMs) of the M4 muscarinic acetylcholine receptor (mAChR) represent a novel approach for treatment psychotic symptoms associated with schizophrenia and other neuropsychiatric disorders. We recently reported that selective PAM VU0152100 produced an antipsychotic drug-like profile in rodents after amphetamine challenge. Previous studies suggest enhanced cholinergic activity may also improve cognitive function reverse deficits observed reduced signaling through...
Herein we describe our initial work on the K2P family of potassium ion channels with chemical optimization and characterization a novel series TWIK-Related K+ Channel (TREK)-1/2 dual activators TREK-2 preferring derived from high-throughput screening hit. The exercise provided TREK good CNS penetration others low exposure to enable exploration both central peripheral activation. From this, ONO-2920632 (VU6011887 = 19b) emerged as reasonably potent (human Tl+; TREK-1 EC50 2.8 μM (95% Emax),...
Previous studies suggest that selective antagonists of specific subtypes muscarinic acetylcholine receptors (mAChRs) may provide a novel approach for the treatment certain central nervous system (CNS) disorders, including epileptic Parkinson9s disease, and dystonia. Unfortunately, previously reported are not highly mAChR subtypes, making it difficult to definitively establish functional roles therapeutic potential individual this receptor subfamily. The M<sub>1</sub> is particular interest...
This report describes the discovery and initial characterization of first positive allosteric modulator muscarinic acetylcholine receptor subtype 5 (mAChR5 or M5). Functional HTS, identified VU0119498, which displayed micromolar potencies for potentiation at M1, M3, M5 receptors in cell-based Ca2+ mobilization assays. Subsequent optimization led to VU0238429, possessed an EC50 approximately 1.16 μM with >30-fold selectivity versus M1 no M2 M4 potentiator activity.
Cholinergic transmission in the forebrain is mediated primarily by five subtypes of muscarinic acetylcholine receptors (mAChRs), termed M(1)-M(5). Of mAChR subtypes, M(1) among most heavily expressed regions that are critical for learning and memory, has been viewed as subtype memory attention mechanisms. Unfortunately, it difficult to develop selective activators other individual which prevented detailed studies functional roles activation M(1). Using a HTS screen subsequent...
Parkinson9s disease (PD) is a debilitating neurodegenerative disorder associated with severe motor impairments caused by the loss of dopaminergic innervation striatum. Previous studies have demonstrated that positive allosteric modulators (PAMs) metabotropic glutamate receptor 4 (mGlu<sub>4</sub>), including <i>N</i>-phenyl-7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxamide, can produce antiparkinsonian-like effects in preclinical models PD. However, these early mGlu<sub>4</sub> PAMs...
Of the five muscarinic receptor subtypes, M 5 is only one detectable in midbrain dopaminergic neurons, making it an attractive potential therapeutic target for treating disorders which signaling disrupted. However, developing understanding of role regulating dopamine neuron function has been hampered by a lack subtype-selective compounds. Here, we extensively characterize novel compound VU0238429 and demonstrate that acts as positive allosteric modulator with unprecedented selectivity...
A functional high throughput screen and subsequent multidimensional, iterative parallel synthesis effort identified the first muscarinic acetylcholine receptor (mAChR) negative allosteric modulator (NAM) selective for M5 subtype. ML375 is a highly NAM with submicromolar potency (human IC50 = 300 nM, rat 790 M1–M4 > 30 μM), excellent multispecies PK, CNS penetration, enantiospecific inhibition.
Rett syndrome (RS) is a neurodevelopmental disorder that shares many symptomatic and pathological commonalities with idiopathic autism. Alterations in protein synthesis-dependent synaptic plasticity (PSDSP) are hallmark of number syndromic forms autism; the present work, we explore consequences disruption rescue PSDSP mouse model RS. We report expression key regulator synthesis, metabotropic glutamate receptor 5 (mGlu
Herein, we report the structure-activity relationships within a series of potent, selective, and orally bioavailable muscarinic acetylcholine receptor 4 (M4) positive allosteric modulators (PAMs). Compound 6c (VU0467485) possesses robust in vitro M4 PAM potency across species vivo efficacy preclinical models schizophrenia. Coupled with an attractive DMPK profile suitable predicted human PK, was evaluated as development candidate.
Herein, we report the structure-activity relationship of a novel series (2(phenoxymethyl)-6,7-dihydrooxazolo[5,4-c]pyridine-5(4H)-yl(aryl)methanones as potent, selective, and orally bioavailable metabotropic glutamate receptor subtype 5 (mGlu5) positive allosteric modulators (PAMs). On basis its robust in vitro potency vivo efficacy multiple preclinical models domains schizophrenia, coupled with good DMPK profile an acceptable therapeutic window, 17a (VU0409551/JNJ-46778212) was selected...