A5059041675- Receptor Mechanisms and Signaling
- Neuroscience and Neuropharmacology Research
- Marine Toxins and Detection Methods
- Marine Sponges and Natural Products
- Pharmacological Receptor Mechanisms and Effects
- X-ray Diffraction in Crystallography
- Crystallization and Solubility Studies
- Pharmacogenetics and Drug Metabolism
- Neurotransmitter Receptor Influence on Behavior
- Oxidative Organic Chemistry Reactions
- Amino Acid Enzymes and Metabolism
- Chemical synthesis and alkaloids
- Chemical Synthesis and Analysis
- Carbohydrate Chemistry and Synthesis
- Biochemical and Molecular Research
- Mass Spectrometry Techniques and Applications
- Ion channel regulation and function
- Synthesis and Catalytic Reactions
- Chemical Reaction Mechanisms
- Asymmetric Synthesis and Catalysis
- Nicotinic Acetylcholine Receptors Study
- Crystallography and molecular interactions
- Drug Transport and Resistance Mechanisms
- Cyclopropane Reaction Mechanisms
- Neuropeptides and Animal Physiology
Shanxi Agricultural University
2025
Yangzhou University
2025
Eli Lilly (United States)
2012-2023
China Pharmaceutical University
2008
Harvard University
2006
Eisai (Japan)
2006
Nagoya University
2006
University of California, San Diego
2003-2004
Scripps Research Institute
2003-2004
University of Minnesota
2001-2002
The uniquely woven, highly strained molecular architecture and the potent antitumor activity of diazonamide A (1) make this natural product an attractive synthetic target. key steps in total synthesis 1 include a novel SmI2-induced ring-closing cascade sequence unusual oxidation indoline to oxindole presence Pd(OH)2/C.
The key flavor compound formation pathways resulting from indigenous microorganisms during the spontaneous fermentation of wine have not been thoroughly described. In this study, high-throughput metagenomic sequencing and untargeted metabolomics were utilized to investigate evolution microbial metabolite profiles in industrial-scale production elucidate mechanisms compounds. Metabolome analysis showed that total amount esters, fatty acids, organic aldehydes, terpenes, flavonoids,...
As an especially unique target for chemical synthesis, diazonamide A has the potential to be constructed through a plethora of synthetic routes, each attended by different challenges and opportunities discovery. In this article, we detail our second total synthesis sequence entirely distinct from that employed in first campaign, one whose success required development several special strategies tactics. We also disclose complete studies regarding biology its structural congeners, more fully...
As part of our ongoing research to identify novel agents acting at metabotropic glutamate 2 (mGlu2) and 3 (mGlu3) receptors, we have previously reported the identification C4α-methyl analog mGlu2/3 receptor agonist 1 (LY354740). This molecule, 1S,2S,4R,5R,6S-2-amino-4-methylbicyclo[3.1.0]hexane-2,6-dicarboxylate (LY541850), exhibited an unexpected mGlu2 agonist/mGlu3 antagonist pharmacological profile, whereas C4β-methyl diastereomer (3) possessed dual activity. We now further explored this...
Identification of orthosteric mGlu(2/3) receptor agonists capable discriminating between individual mGlu2 and mGlu3 subtypes has been highly challenging owing to the glutamate-site sequence homology these proteins. Herein we detail preparation characterization a series molecules related (1S,2S,5R,6S)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate 1 (LY354740) bearing C4-thiotriazole substituents. On basis second messenger responses in cells expressing other recombinant human mGlu2/3 subtypes,...
Clinical development of catechol-based orthosteric agonists the dopamine D1 receptor has thus far been unsuccessful due to multiple challenges. To address these issues, we identified LY3154207 (3) as a novel, potent, and subtype selective human positive allosteric modulator (PAM) with minimal agonist activity. Conformational studies showed adopts an unusual boat conformation, binding pose was proposed based on this observation. In contrast agonists, distinct pharmacological profile without...
DETQ, an allosteric potentiator of the dopamine D1 receptor, was tested in therapeutic models that were known to respond agonists. Because a species difference affinity for all rodent experiments used transgenic mice expressing human receptor (hD1 mice). When given alone, DETQ reversed locomotor depression caused by low dose reserpine. also acted synergistically with L-DOPA reverse strong hypokinesia seen higher These results indicate potential as both monotherapy and adjunct treatment...
Allosteric potentiators amplify the sensitivity of physiologic control circuits, a mode action that could provide therapeutic advantages. This hypothesis was tested with dopamine D1 receptor potentiator DETQ [2-(2,6-dichlorophenyl)-1-((1S,3R)-3-(hydroxymethyl)-5-(2-hydroxypropan-2-yl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one]. In human embryonic kidney 293 (HEK293) cells expressing receptor, induced 21-fold leftward shift in cAMP response to dopamine, Kb 26 nM. The maximum alone...
The binding site for DETQ [2-(2,6-dichlorophenyl)-1-((1<i>S</i>,3<i>R</i>)-3-(hydroxymethyl)-5-(2-hydroxypropan-2-yl)-1-methyl-3,4-dihydroisoquinolin-2(1<i>H</i>)-yl)ethan-1-one], a positive allosteric modulator (PAM) of the dopamine D1 receptor, was identified and compared with CID 2886111 [<i>N</i>-(6-<i>tert</i>-butyl-3-carbamoyl-4,5,6,7-tetrahydro-1-benzothiophen-2-yl)pyridine-4-carboxamide], reference PAM. From D1/D5 chimeras, responsible potentiation by increase in cAMP response to...
A stereocontrolled synthesis of the C26–C40 domain azaspiracid shellfish toxins containing intricate FGHI ring system has been achieved by deployment novel methods for heterocycle (see scheme). Boc=tert-butoxycarbonyl, TBS=tert-butyldimethylsilyl.
A unified total synthesis is reported to access all of the possible diastereomers pteriatoxins A−C, with use an intramolecular Diels−Alder reaction as key step form carbo-macrocyclic core structure. The C34/C35-diol protecting groups were found have significant effects on both exo/endo-selectivity and exo-facial selectivity process.
[structure: see text]. An effective approach to form a 1,3-disubstituted 2,9-dioxabicyclo[3.3.1]nonane system representing the core of F and G rings (C28-C34) azaspiracid natural products has been developed. The double intramolecular hetero-Michael addition (DIHMA) diol upon an ynone generated bicyclic ketal in highly diastereoselective fashion.
ADVERTISEMENT RETURN TO ISSUEPREVCommunicationNEXTStereochemistry of Pteriatoxins A, B, and CJunliang Hao, Fumiyoshi Matsuura, Yoshito Kishi, Masaki Kita, Daisuke Uemura, Naoki Asai, Takashi IwashitaView Author Information Department Chemistry Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, Research Center for Materials Science, Nagoya Chikusa, Nagoya, Japan, Chemistry, Graduate School Tsukuba Laboratories, Eisai Pharmaceutical Company, Tsukuba, Suntory Institute...
Multiple therapeutic opportunities have been suggested for compounds capable of selective activation metabotropic glutamate 3 (mGlu3) receptors, but small molecule tools are lacking. As part our ongoing efforts to identify potent, selective, and systemically bioavailable agonists mGlu2 mGlu3 receptor subtypes, a series C4β-N-linked variants (1S,2S,5R,6S)-2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 1 (LY354740) were prepared evaluated both binding affinity functional cellular...
Pinnatoxins B and C were synthesized from diols (34R)-3b (34S)-3a, respectively, in a stereochemically controlled manner. Through extensive analysis of the 1H NMR spectra synthetic PnTXs C, diagnostic signals first identified to differentiate (34S)- (34R)-diastereomers then used establish C34 configuration natural as 34S 34R, respectively.
As part of our ongoing interest in identifying novel agonists acting at metabotropic glutamate (mGlu) 2/3 receptors, we have explored the effect structural modifications 1S,2S,5R,6S-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate (LY354740), a potent and pharmacologically balanced mGlu2/3 receptor agonist. Incorporation relatively small substituents (e.g., F, O) C4 position this molecule resulted additional highly that demonstrate excellent selectivity over other mGlu subtypes, while addition...
The evolution from early medicinal chemistry to large-scale production of the chemical synthesis Lilly D1-positive allosteric modulator (PAM) mevidalen (LY3154207) and its hydroxybenzoate co-crystal is outlined. issues steps taken resolve them are outlined across several generations synthesis, including unexpected that arose during cryogenic addition MeLi a key imine intermediate use flow enable production. Ultimately, process was used deliver >100 kg API support ongoing clinical trials described.