Jamie S. Simpson

Bio: Jamie S. Simpson is an academic researcher from Monash University. The author has contributed to research in topics: Prodrug & DsbA. The author has an hindex of 23, co-authored 67 publications receiving 1412 citations. Previous affiliations of Jamie S. Simpson include Monash University, Parkville campus & Australian National University.

Neurokinin 1 receptor signaling in endosomes mediates sustained nociception and is a viable therapeutic target for prolonged pain relief

Abstract: Typically considered to be cell surface sensors of extracellular signals, heterotrimeric GTP-binding protein (G protein)-coupled receptors (GPCRs) control many pathophysiological processes and are the target of 30% of therapeutic drugs Activated receptors redistribute to endosomes, but researchers have yet to explore whether endosomal receptors generate signals that control complex processes in vivo and are viable therapeutic targets We report that the substance P (SP) neurokinin 1 receptor (NK1R) signals from endosomes to induce sustained excitation of spinal neurons and pain transmission and that specific antagonism of the NK1R in endosomes with membrane-anchored drug conjugates provides more effective and sustained pain relief than conventional plasma membrane-targeted antagonists Pharmacological and genetic disruption of clathrin, dynamin, and β-arrestin blocked SP-induced NK1R endocytosis and prevented SP-stimulated activation of cytosolic protein kinase C and nuclear extracellular signal-regulated kinase, as well as transcription Endocytosis inhibitors prevented sustained SP-induced excitation of neurons in spinal cord slices in vitro and attenuated nociception in vivo When conjugated to cholestanol to promote endosomal targeting, NK1R antagonists selectively inhibited endosomal signaling and sustained neuronal excitation Cholestanol conjugation amplified and prolonged the antinociceptive actions of NK1R antagonists These results reveal a critical role for endosomal signaling of the NK1R in the complex pathophysiology of pain and demonstrate the use of endosomally targeted GPCR antagonists

Promiscuous 2-aminothiazoles (PrATs): a frequent hitting scaffold.

Abstract: We have identified a class of molecules, known as 2-aminothiazoles (2-ATs), as frequent-hitting fragments in biophysical binding assays. This was exemplified by 4-phenylthiazol-2-amine being identified as a hit in 14/14 screens against a diverse range of protein targets, suggesting that this scaffold is a poor starting point for fragment-based drug discovery. This prompted us to analyze this scaffold in the context of an academic fragment library used for fragment-based drug discovery (FBDD) and two larger compound libraries used for high-throughput screening (HTS). This analysis revealed that such “promiscuous 2-aminothiazoles” (PrATs) behaved as frequent hitters under both FBDD and HTS settings, although the problem was more pronounced in the fragment-based studies. As 2-ATs are present in known drugs, they cannot necessarily be deemed undesirable, but the combination of their promiscuity and difficulties associated with optimizing them into a lead compound makes them, in our opinion, poor scaffolds for...

Self-Assembled Nanoreactors

Abstract: An overview of the wide range of nanoreactors that have been constructed from synthetic and biological building blocks using both covalent and noncovalent approaches is given. Focus is on self-assembled systems, varying in size from a few nanometers to tens of micrometers. The review is divided into several sections that cover the development of tailor-made nanoreactors, starting from small organic molecular containers expanding to large compartment-containing assemblies. First, the construction of capsules from low molecular weight compounds by means of covalent synthesis and self-assembly by highly directive and pre-designed interactions is discussed. Second, nanocapsules based on micellar and vesicular assemblies that are built up frow low molecular weight molecules are described. Finally, the construction of nanoreactors from macromolecular building blocks, as well as recent developments in the use of viruses as nanocontainers and reactors are outlined.

Destruction and Detection of Chemical Warfare Agents

Abstract: 1. Scope of Article and Previous Related Reviews 5346 2. Introduction 5346 2.1. Destruction 5347 2.2. Sensing 5347 2.3. Historical Context 5348 2.3.1. Brief History and Molecular Structure 5348 2.4. Related Compounds and Nomenclature 5348 2.4.1. Phosphorus(V) Parent Compounds and Fundamental Chemistry 5348 2.4.2. Pesticides 5349 2.4.3. Simulants 5349 2.4.4. Decomposition Products 5350 2.5. Toxicology 5351 2.5.1. Acetylcholine Esterase (AChE) Inhibition 5351 2.5.2. Endocannabinoid System Activation 5352 2.6. Critical Needs To Decontaminate and Detect 5353 2.7. Treaties and Conventions 5354 3. Stockpile Destruction 5355 3.1. Agent Storage 5355 3.2. Protection Protocols and Logistics 5355 3.3. Background 5355 3.4. Methods Currently Employed 5355 3.4.1. Incineration 5355 3.4.2. Neutralization by Base Hydrolysis 5356 4. Decomposition Reactions 5357 4.1. Hydrolysis 5357 4.2. Autocatalytic Hydrolysis or Hydrolysis Byproducts 5358 4.3. Use of Peroxide 5359 4.4. Oxidation with Bleach and Related Reagents 5360 4.5. Alkoxide as Nucleophile 5360 4.5.1. Basic Media 5360 4.5.2. Metal-Catalyzed Reactions 5361 4.5.3. Metal-Assisted Reactions 5363 4.5.4. Biotechnological Degradation 5363 4.5.5. Cyclodextrin-Assisted Reactions 5370 4.6. Halogen as the Nucleophile 5370 4.6.1. Use of BrOx 5370 4.6.2. Use of Other Halogens 5371 4.6.3. Use of Group 13 Chelates 5371 4.7. Surface Chemistry 5371 4.7.1. Bare Metals and Solid Nanoparticles 5371 4.7.2. Metal Oxides 5371 4.7.3. Representative Elements 5372 4.7.4. d-Block (Groups 4 10) 5373 4.7.5. Solid Metal Oxides of Group 3 and the Lanthanides 5375 4.7.6. Porous Silicon and Related Systems 5375 4.7.7. Zeolites 5375 4.7.8. Comparative IR Data 5375 4.8. Other Types of Systems 5375 5. Decontamination 5376 5.1. Overview: Ability to React with All Types of Agents, Ease of Application, and Compatibility with Treated Objects 5376 6. Agent Fate and Disposal 5378 6.1. Indoor 5378 6.2. Concrete and Construction Surfaces 5378 6.3. Landfills 5379 7. Sensing and Detection 5379 7.1. Possible Metal Ion Binding Modes in Solution 5379 7.1.1. Early Reports of Phosph(on)ate [R3PdO 3 3 3M nþ] Interactions (R= Alkyl, Alkoxyl) 5380 7.1.2. Coordination Chemistry of Downstream Non-P-Containing Products of Decomposition 5380 7.2. Colorimetric Detection 5381 7.3. Chemiluminescence: Fluorescence and Phosphorescence 5382 7.3.1. Lanthanide-Based Catalysts 5382 7.3.2. Organometallic-Based Sensors 5382 7.3.3. Organic Design 5382 7.3.4. Biologically-Based Luminescence Detection 5382 7.3.5. Polymer and Bead Supports 5382 7.4. Porous Silicon 5383 7.5. Carbon Nanotubes 5383

Small Heterocycles in Multicomponent Reactions

Abstract: Benjamin H. Rotstein,†,‡ Serge Zaretsky,† Vishal Rai,†,§ and Andrei K. Yudin*,† †Davenport Research Laboratories, Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, Ontario Canada, M5S 3H6 ‡Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital, and Department of Radiology, Harvard Medical School, 55 Fruit Street, Boston, Massachusetts 02114, United States Department of Chemistry, Indian Institute of Science Education and Research (IISER) Bhopal, Indore By-pass Road, Bhauri, Bhopal 462 066, MP India