A5066799481- Receptor Mechanisms and Signaling
- Neuroscience and Neuropharmacology Research
- Cholinesterase and Neurodegenerative Diseases
- Phosphodiesterase function and regulation
- Pharmacological Receptor Mechanisms and Effects
- Photoreceptor and optogenetics research
- Neuropeptides and Animal Physiology
- Parkinson's Disease Mechanisms and Treatments
- Cardiac electrophysiology and arrhythmias
- Medical Imaging Techniques and Applications
- Genetics and Neurodevelopmental Disorders
- Chemical Synthesis and Analysis
- Radiopharmaceutical Chemistry and Applications
- Mass Spectrometry Techniques and Applications
- Synthesis and Properties of Aromatic Compounds
- Ion channel regulation and function
Vanderbilt University
2016-2025
Vanderbilt University Medical Center
2014
The metabotropic glutamate receptor 7 (mGlu7) is a G protein–coupled that has been recently linked to neurodevelopmental disorders. This association supported by the identification of GRM7 variants in patients with autism spectrum disorder, attention deficit hyperactivity and severe developmental delay. One mutation previously reported 2 results single amino acid change, I154T, within mGlu7 ligand-binding domain. Here, we report new this who present delay epilepsy. Functional studies...
Herein, we report the further chemical optimization of metabotropic glutamate receptor subtype 1 (mGlu1) positive allosteric modulator (PAM) VU6024578/BI02982816 and discovery VU6033685/BI1752. PAM VU6033685/BI1752 was developed through an iterative process wherein, after furanyl moiety (a potential toxicophore) replaced by N-linked pyrazole, a diversity screen identified quinoline core, which truncated to pyridine scaffold. proved be potent selective mGlu1 with efficacy in both...
The development of cholinergic neurotransmitter based cognitive enhancers for Alzheimer's disease and other neuropsychiatric disorders have focused recently on allosteric modulation specific muscarinic acetylcholine receptor (mAChR) subtypes to reduce dose-limiting side-effects that been the hallmark earlier orthosteric mAChR agonists. VU0467319 (VU319) is an investigational positive modulator M 1 mAChR. A Phase first-in-human study was conducted assessing safety brain activity utilizing...
This Letter describes the discovery of novel mGlu5 NAMs VU6031545 and VU6024945. Starting from previously reported picolinamide compounds, a structure-activity relationship study various core isosteres was conducted, leading to identification thieno[3,2-b]pyridine-5-carboxamide 2,3-difluorobenzamide as competent replacements. These compounds are highly potent well brain penetrant with an IVIVC agreement improved oral bioavailability in rats.
Herein we report progress toward a backup clinical candidate to the M1 positive allosteric modulator (PAM) VU319/ACP-319. Scaffold-hopping from pyrrolo[2,3-b]pyridine-based PAM VU6007477 isomeric pyrrolo[3,2-b]pyridine and thieno[3,2-b]pyridine congeners identified several contenders. Ultimately, VU6007496, pyrrolo[3,2-b]pyridine, advanced into late stage profiling, only be plagued with unanticipated, species-specific metabolism active/toxic metabolites which were in our phenotypic seizure...
Herein, we report progress toward a metabotropic glutamate receptor subtype 1 (mGlu
In the course of optimizing an M1 PAM chemotype, introduction ether moiety unexpectedly abolished activity while engendering a "molecular switch" to afford weak, pure mGlu5 PAM. Further optimization was able deliver potent (mGlu5 EC50 = 520 nM, 63% Glu Max), centrally penetrant (Kp 0.83), MPEP-site binding 17a (VU6036486) that reversed amphetamine-induced hyperlocomotion. A pronounced "magic methyl" effect noted with regioisomeric methyl congener, leading change in pharmacology IC50 110 3%...
Non-selective antagonists of muscarinic acetylcholine receptors (mAChRs) that broadly inhibit all five mAChR subtypes provide an efficacious treatment for some movement disorders, including Parkinson's disease and dystonia. Despite their efficacy in these other central nervous system anti-muscarinic therapy has limited utility due to severe adverse effects often limit tolerability by patients. Recent advances understanding the roles each subtype plays pathology suggest highly selective...