A5047118594- Receptor Mechanisms and Signaling
- Neuroscience and Neuropharmacology Research
- Neuropeptides and Animal Physiology
- Nicotinic Acetylcholine Receptors Study
- Pharmacological Receptor Mechanisms and Effects
- Chemical Synthesis and Analysis
- Mass Spectrometry Techniques and Applications
- Diabetes Treatment and Management
- Nonlinear Optical Materials Research
- Phosphodiesterase function and regulation
- Nitric Oxide and Endothelin Effects
- Bioactive Compounds and Antitumor Agents
- Protein Kinase Regulation and GTPase Signaling
- Monoclonal and Polyclonal Antibodies Research
- X-ray Diffraction in Crystallography
- Ion channel regulation and function
- Computational Drug Discovery Methods
- Biosimilars and Bioanalytical Methods
- Cancer therapeutics and mechanisms
- Photochromic and Fluorescence Chemistry
- Advanced Electron Microscopy Techniques and Applications
- Analytical Chemistry and Chromatography
- TGF-β signaling in diseases
- Angiogenesis and VEGF in Cancer
- Muon and positron interactions and applications
Australian Regenerative Medicine Institute
2025
Monash University
2015-2025
ENVIRON (United States)
2024
University of Copenhagen
2019-2023
Vanderbilt University
2009-2018
Vanderbilt University Medical Center
2008-2016
Institute of Pharmacology
2014
VA Tennessee Valley Healthcare System
2014
The therapeutic potential of small molecule signaling inhibitors is often limited by off-target effects. Recently, in a screen for compounds that perturb the zebrafish embryonic dorsoventral axis, we identified dorsomorphin, first selective inhibitor bone morphogenetic protein (BMP) signaling. Here show dorsomorphin has significant "off-target" effects against VEGF (vascular endothelial growth factor) type-2 receptor (Flk1/KDR) and disrupts angiogenesis. Since both BMP signals are known to...
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,...
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.
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...
The human M 5 muscarinic acetylcholine receptor (mAChR) has recently emerged as an exciting therapeutic target for treating a range of disorders, including drug addiction. However, lack structural information this subtype limited further development and validation. Here we report high-resolution crystal structure the mAChR bound to clinically used inverse agonist, tiotropium. This allowed comparison across all family members that revealed important differences in both orthosteric allosteric...
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.
A duplexed, functional multiaddition high throughput screen and subsequent iterative parallel synthesis effort identified the first highly selective CNS penetrant glucagon-like peptide-1R (GLP-1R) positive allosteric modulator (PAM). PAM (S)-9b potentiated low-dose exenatide to augment insulin secretion in primary mouse pancreatic islets, alone was effective potentiating endogenous GLP-1R reverse haloperidol-induced catalepsy.
An iterative analogue library synthesis strategy rapidly developed comprehensive SAR data for a novel series of M4 positive allosteric modulators (PAMs). This effort identified key moieties that improved microsomal stability and physiochemical properties. Moreover, this displayed an order magnitude greater potency human versus rat M4, providing compounds with EC50 values in the 100 nM range.
Abstract Of the five G‐protein‐coupled muscarinic acetylcholine receptors (mAChRs; M 1 –M 5 ), is least explored and understood due to a lack of mAChR subtype‐selective ligands. We recently performed high‐throughput functional screen identified number weak antagonist hits that are selective for receptor. Here, we report an iterative parallel synthesis detailed molecular pharmacologic profiling effort led discovery first highly selective, central nervous system (CNS)‐penetrant ‐orthosteric...
Recently, the first subtype-selective allosteric modulators of M<sub>5</sub> muscarinic acetylcholine receptor (mAChR) have been described, but their molecular mechanisms action remain unknown. Using radioligand-binding and functional assays inositol phosphate (IP) accumulation Ca<sup>2+</sup> mobilization in a recombinant cell line stably expressing human mAChR, we investigated effects positive modulator (PAM), ML380, negative modulator, ML375. In assays, ML380 caused robust enhancements...
Abstract The M 5 muscarinic acetylcholine receptor (M mAChR) represents a promising therapeutic target for neurological disorders. However, the high conservation of its orthosteric binding site has posed significant challenges drug development. While selective positive allosteric modulators (PAMs) offer potential solution, structural understanding mAChR and sites remained limited. Here, we present 2.8 Å cryo-electron microscopy structure complexed with heterotrimeric G q protein agonist...
A functional high throughput screen identified a novel chemotype for the positive allosteric modulation (PAM) of muscarinic acetylcholine receptor (mAChR) subtype 5 (M5). Application rapid analog, iterative parallel synthesis efficiently optimized M5 potency to arrive at most potent PAMs prepared date and provided tool compound 8n (ML380) demonstrating modest CNS penetration (human EC50 = 190 nM, rat 610 brain plasma ratio (Kp) 0.36).
The orphan G protein-coupled receptor GPR139 is predominantly expressed in the central nervous system and has attracted considerable interest as a therapeutic target. However, biological role of this remains somewhat elusive, part due to lack quality pharmacological tools investigate function. In an effort understand signaling identify improved compounds, study we performed virtual screening analog searches, combination with multiple assays. We characterized GPR139-dependent using previously...