A5103131732- Receptor Mechanisms and Signaling
- Neuropeptides and Animal Physiology
- Chemical Synthesis and Analysis
- Peptidase Inhibition and Analysis
- Cellular transport and secretion
- Biochemical effects in animals
- Glycosylation and Glycoproteins Research
- Synthesis and Catalytic Reactions
- Amino Acid Enzymes and Metabolism
- Ubiquitin and proteasome pathways
- Neurotransmitter Receptor Influence on Behavior
- Nuclear Receptors and Signaling
- Cancer, Stress, Anesthesia, and Immune Response
- Estrogen and related hormone effects
- Synthesis and Reactivity of Sulfur-Containing Compounds
- Pharmacological Receptor Mechanisms and Effects
- Spaceflight effects on biology
- Molecular Sensors and Ion Detection
- Organic Chemistry Cycloaddition Reactions
- Chemical Reaction Mechanisms
- S100 Proteins and Annexins
- Neuroscience and Neuropharmacology Research
- Cellular Mechanics and Interactions
- Axial and Atropisomeric Chirality Synthesis
- Tryptophan and brain disorders
Biocon (India)
2023
Heptares Therapeutics (United Kingdom)
2022-2023
Syngene International (India)
2023
Lundbeck (Denmark)
2013-2015
GlaxoSmithKline (United Kingdom)
2010-2012
University of Hertfordshire
1995-1996
Episodic memory deficits are a core feature of neurodegenerative disorders. Muscarinic M(1) receptors play critical role in modulating learning and highly expressed the hippocampus. We examined effect GSK1034702, potent receptor allosteric agonist, on cognitive function, particular episodic memory, healthy smokers using nicotine abstinence model dysfunction. The study utilized randomized, double-blind, placebo-controlled, cross-over design which 20 male abstained were tested following single...
HTL0041178 (1), a potent GPR52 agonist with promising pharmacokinetic profile and exhibiting oral activity in preclinical models, has been identified. This molecule was the outcome of judicious molecular property-based optimization approach, focusing on balancing potency against metabolic stability, solubility, permeability, P-gp efflux.
We describe an efficient and general strategy for the synthesis of dimethyl acetal functionalised steroidal hydrazides based on cholic acid skeleton with aim using these compounds as building blocks dynamic combinatorial chemistry. Deprotection protected TFA leads to formation libraries containing macrocyclic N-acyl hydrazone oligomers. The isolation several these, their characterisation NMR is described. effects equilibrium library distribution by varying substituents at C-7 C-12, extending...
A series of macrocyclic calcitonin gene-related peptide (CGRP) receptor antagonists identified using structure-based design principles, exemplified by HTL0028016 (1) and HTL0028125 (2), is described. Structural characterization X-ray crystallography the interaction two macrocycle with CGRP ectodomain described, along structure–activity relationships associated point changes to antagonists. The identification non-peptidic/natural product-derived, ligands for a G protein coupled (GPCR) noteworthy.
Variable temperature 13C NMR investigations reveal that the N-acyl oxaziridine system can exhibit two independent stereodynamic processes: nitrogen inversion becomes slow on timescale at ca.–20 °C (ΔG‡ 10.9–11.9 kcal mol–1) and ca.–60 rotation about N–C(O) bond also 10.2 mol–1).
X-ray crystal structure determinations are reported for 2-diphenylphosphinoyl-3,3-dimethyl- and 3-ethyl-3-methyloxaziridines, 2a 2b, prepared from acetone butanone via the oximes. The P–N bond lengths, 1.722(3) 1.702(5)Å, conformation about this bond, consistent with an n–σ*π-bonding interaction. Steric interactions appear to influence angles at pyramidal nitrogen. Oxaziridine 2b is a mixture of cis trans isomers (ratio ca. 1 : 3) in solution. 1H, 13C 31P NMR spectra discussed. barriers...
The diastereomeric macrocyclic calcitonin gene-related peptide (CGRP) antagonists HTL0029881 (3) and HTL0029882 (4), in which the stereochemistry of a spiro center is reversed, surprisingly demonstrate comparable potency. X-ray crystallographic characterization demonstrates that 3 binds to CGRP receptor precedented manner but 4 an unprecedented, unexpected, radically different manner. observation this phenomenon noteworthy may open novel avenues for antagonist design.
Abstract The title antagonist (I) shows excellent bioavailability in rats and demonstrates brain exposure.
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