A5039200272- Receptor Mechanisms and Signaling
- Neuropeptides and Animal Physiology
- Neuroscience and Neuropharmacology Research
- Neurotransmitter Receptor Influence on Behavior
- Nicotinic Acetylcholine Receptors Study
- Adenosine and Purinergic Signaling
- Monoclonal and Polyclonal Antibodies Research
- Pharmacological Receptor Mechanisms and Effects
- Sleep and Wakefulness Research
- Diabetes Treatment and Management
- Protein Kinase Regulation and GTPase Signaling
- Computational Drug Discovery Methods
- Chemical Synthesis and Analysis
- Sleep and related disorders
- Circadian rhythm and melatonin
- Mast cells and histamine
- Ion channel regulation and function
- Tryptophan and brain disorders
- Pancreatic function and diabetes
- Synthesis and Characterization of Heterocyclic Compounds
- Psychedelics and Drug Studies
- Pharmacogenetics and Drug Metabolism
- Regulation of Appetite and Obesity
- Treatment of Major Depression
- Bone health and treatments
Monash University
2016-2025
Monash Medical Centre
2023-2025
Discovery Centre
2025
Australian Regenerative Medicine Institute
2014-2023
Eli Lilly (United Kingdom)
2018
University of Glasgow
2018
Eli Lilly (United States)
2018
Plateforme Technologique d'Innovation Biomédicale
2017
Servier (France)
2016-2017
The University of Melbourne
2005-2016
Potent, ligand efficient, selective, and orally efficacious 1,2,4-triazine derivatives have been identified using structure based drug design approaches as antagonists of the adenosine A(2A) receptor. The X-ray crystal structures compounds 4e 4g bound to GPCR illustrate that molecules bind deeply inside orthosteric binding cavity. In vivo pharmacokinetic efficacy data for compound 4k are presented, demonstrating potential this series treatment Parkinson's disease.
Virtual screening was performed against experimentally enabled homology models of the adenosine A(2A) receptor, identifying a diverse range ligand efficient antagonists (hit rate 9%). By use docking and Biophysical Mapping (BPM), hits 1 5 were optimized to potent selective lead molecules (11-13 from 5, pK(I) = 7.5-8.5, 13- >100-fold versus A(1); 14-16 1, 7.9-9.0, 19- 59-fold selective).
1. This study characterises the binding of a novel nonpeptide antagonist radioligand, [(3)H]SB-674042 (1-(5-(2-fluoro-phenyl)-2-methyl-thiazol-4-yl)-1-((S)-2-(5-phenyl-(1,3,4)oxadiazol-2-ylmethyl)-pyrrolidin-1-yl)-methanone), to human orexin-1 (OX(1)) receptor stably expressed in Chinese hamster ovary (CHO) cells both whole cell assay and membrane-based scintillation proximity (SPA) format. 2. Specific was saturable membrane formats. Analyses suggested single high-affinity site, with K(d)...
M1 muscarinic ACh receptors (mAChRs) represent an attractive drug target for the treatment of cognitive deficits associated with diseases such as Alzheimer's disease and schizophrenia. However, discovery subtype-selective mAChR agonists has been hampered by high degree conservation orthosteric ACh-binding site among subtypes. The advent functional screening assays enabled identification AC-42 (4-n-butyl-1-[4-(2-methylphenyl)-4-oxo-1-butyl]-piperidine), which bind to allosteric selectively...
The M<sub>2</sub> muscarinic acetylcholine receptor (mAChR) possesses at least one binding site for allosteric modulators that is dependent on the residues <sup>172</sup>EDGE<sup>175</sup>, Tyr<sup>177</sup>, and Thr<sup>423</sup>. However, contribution of these to actions agonists, as opposed modulators, unknown. We created mutant mAChRs in which charge <sup>172</sup>EDGE<sup>175</sup> sequence had been neutralized each Tyr<sup>177</sup> Thr<sup>423</sup> was substituted with alanine....
Using isolated receptor conformations crystal structures of the adenosine A<sub>2A</sub> have been solved in active and inactive states. Studying change affinity ligands at these allowed qualitative prediction compound efficacy vitro a system-independent manner. Agonist 5′-<i>N</i>-ethylcarboxamidoadenosine displayed clear preference to bind state receptor; inverse agonists (xanthine amine congener, ZM241385, SCH58261, preladenant) bound preferentially state, whereas neutral antagonists...
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...
4-n-Butyl-1-[4-(2-methylphenyl)-4-oxo-1-butyl]-piperidine hydrogen chloride (AC-42) is a selective agonist of the muscarinic M(1) receptor previously suggested to interact with an "ectopic" site on this receptor. However, pharmacological properties (i.e., whether it overlaps any extent classic orthosteric or represents novel allosteric site) remain undetermined. In present study, atropine pirenzepine significantly inhibited ability either carbachol AC-42 stimulate inositol phosphate...
Orexin receptor antagonism represents a novel approach for the treatment of insomnia that directly targets sleep/wake regulation. Several such compounds have entered into clinical development, including dual orexin antagonists, suvorexant and almorexant. In this study, we used equilibrium kinetic binding studies with orexin-2 (OX₂) selective antagonist radioligand, [³H]-EMPA, to profile several antagonists. Furthermore, selected were studied in cell-based assays inositol phosphate...
Phenotyping of Gprc6a KO mice has shown that this promiscuous class C G protein coupled receptor is variously involved in regulation metabolism, inflammation and endocrine function. Such effects are described as mediated by extracellular calcium, L-amino acids, the bone-derived peptide osteocalcin (OCN) male hormone testosterone, introducing concept a bone-energy-metabolism-reproduction functional crosstalk GPRC6A. However, whilst calcium acid-sensing properties GPRC6A well established,...
Orexins are neuropeptides that activate the rhodopsin-like G protein-coupled receptors OX1R and OX2R. The orexin system plays an important role in regulation of sleep-wake cycle feeding emotions. nonselective receptor antagonist suvorexant has been first drug on market targeting is prescribed for treatment insomnia. Subtype-selective antagonists valuable tools to further investigate functions physiological vivo promising lead compounds addiction, anxiety, pain or obesity. Starting from OX2R...
Recent years have witnessed the discovery of novel selective agonists M<sub>1</sub> muscarinic acetylcholine (ACh) receptor (mAChR). One mechanism invoked to account for selectivity such agents is that they interact with allosteric sites. We investigated molecular pharmacology two agonists, 1-[3-(4-butyl-1-piperidinyl)propyl]-3,4-dihydro-2(1<i>H</i>)-quinolinone (77-LH-28-1) and 4-<i>n</i>-butyl-1-[4-(2-methylphenyl)-4-oxo-1-butyl] piperidine hydrogen chloride (AC-42), at wild-type mAChR...
Positive and negative allosteric modulators (PAMs NAMs, respectively) of the type 5 metabotropic glutamate (mGlu5) receptor have demonstrable therapeutic potential in an array neurological psychiatric disorders. Here, we used rat cortical astrocytes to investigate how PAMs NAMs mediate their activity reveal marked differences between with respect modulation orthosteric agonist affinity efficacy. Affinity cooperativity factors (α) were assessed using...