A5067184628- Receptor Mechanisms and Signaling
- Neurotransmitter Receptor Influence on Behavior
- Pharmacological Receptor Mechanisms and Effects
- Neuropeptides and Animal Physiology
- Neuroscience and Neuropharmacology Research
- Crystallization and Solubility Studies
- X-ray Diffraction in Crystallography
- Pain Mechanisms and Treatments
- Pharmacological Effects and Assays
- Computational Drug Discovery Methods
- Synthesis and Biological Evaluation
- Click Chemistry and Applications
- Attention Deficit Hyperactivity Disorder
- Chemical Synthesis and Analysis
- Cannabis and Cannabinoid Research
- Crystallography and molecular interactions
- Pharmacological Effects and Toxicity Studies
- Treatment of Major Depression
- Neurogenesis and neuroplasticity mechanisms
- Political Conflict and Governance
- Ion Transport and Channel Regulation
- Adenosine and Purinergic Signaling
- Law, Rights, and Freedoms
- interferon and immune responses
- Opioid Use Disorder Treatment
Rowan University
2015-2024
Syracuse University
2022-2023
National Institutes of Health
2012-2021
National Institute on Drug Abuse
2012-2021
Cooper Medical School of Rowan University
2019-2020
Open Targets
2013
Oregon Health & Science University
2005-2012
German Cancer Research Center
1998
Heidelberg University
1998
The dopamine D3 receptor (D3R) is a target for developing medications to treat substance use disorders. D3R-selective compounds with high affinity and varying efficacies have been discovered, providing critical research tools cell-based studies that translated in vivo models of drug abuse. D3R antagonists partial agonists shown especially promising results rodent relapse-like behavior, including stress-, drug-, cue-induced reinstatement seeking. However, date, translation human has limited....
The recent and precipitous increase in opioid analgesic abuse overdose has inspired investigation of the dopamine D3 receptor (D3R) as a target for therapeutic intervention. Metabolic instability or predicted toxicity precluded successful translation previously reported D3R-selective antagonists to clinical use cocaine abuse. Herein, we report series novel D3R crystal structure-guided 4-phenylpiperazines with exceptionally high affinities and/or selectivities varying efficacies. Lead...
Both dopamine D3 receptor (D3R) partial agonists and antagonists have been implicated as potential medications for substance use disorders. In contrast to antagonists, may cause fewer side effects since they maintain some dopaminergic tone be less disruptive normal neuronal functions. Here, we report three sets of 4-phenylpiperazine stereoisomers that differ considerably in efficacy: the (R)-enantiomers are antagonists/weak agonists, whereas (S)-enantiomers much more efficacious. To...
Viral infection activates interferon regulatory factor 3 (IRF3), a cofactor for the induction of interferon-stimulated genes (ISGs). The role IRF3 in activation ISGs by human cytomegalovirus (HCMV) is controversial despite fact that HCMV has consistently been shown to induce during fibroblasts. To address function HCMV-mediated ISG induction, we monitored expression and global gene HCMV-infected cells which had depleted small interfering RNA or blocked dominant negative IRF3. A specific...
We report a class of potent and selective dopamine D3 receptor antagonists based upon tranylcypromine. Although tranylcypromine has low affinity for the rat (K(i) = 12.8 μM), our efforts have yielded (1R,2S)-11 (CJ-1882), which K(i) values 2.7 2.8 nM at human receptors, respectively, displays respective selectivities >10000-fold 223-fold over D2 receptors. Evaluation in β-arrestin functional assay showed that is competitive antagonist receptor.
The dopamine D3 receptor (D3R) is a promising target for the development of pharmacotherapeutics to treat substance use disorders. Several D3R-selective antagonists are effective in animal models drug abuse, especially relapse. Nevertheless, poor bioavailability, metabolic instability, and/or predicted toxicity have impeded success translating these candidates clinical use. Herein, we report series 4-phenylpiperazines with improved stability. A subset compounds was evaluated D3R functional...
The development of bitopic ligands directed toward D2-like receptors has proven to be particular interest improve the selectivity and/or affinity these and as an approach modulate bias their efficacies. structural similarities between dopamine D3 receptor (D3R)-selective molecules that display or allosteric pharmacology those are simply competitive antagonists subtle intriguing. Herein we synthesized a series in which primary secondary pharmacophores were derived from D3R-selective SB269,652...
Abstract To understand how distinct memories are formed and stored in the brain is an important fundamental question neuroscience computational biology. A population of neurons, termed engram cells, represents physiological manifestation a specific memory trace characterized by dynamic changes gene expression, which turn alters synaptic connectivity excitability these cells. Recent applications single-cell RNA sequencing (scRNA-seq) single-nucleus (snRNA-seq) promising approaches for...
Abstract Pre‐clinical studies suggest that negative allosteric modulators ( NAMs ) of the metabotropic glutamate receptor subtype 5 mGluR5 ), including 2‐methyl‐6‐(phenylethynyl)pyridine MPEP 3‐[(2‐methyl‐1,3‐thiazol‐4‐yl)ethynyl]pyridine MTEP and fenobam are highly effective in attenuating drug‐taking drug‐seeking behaviors. However, both have no translational potential for use humans because their off‐target effects short half‐lives. Here, we report...
Novel 1-, 5-, and 8-substituted analogues of sumanirole (1), a dopamine D2/D3 receptor (D2R/D3R) agonist, were synthesized. Binding affinities at both D2R D3R higher when determined in competition with the agonist radioligand [3H]7-hydroxy-N,N-dipropyl-2-aminotetralin (7-OH-DPAT) than antagonist [3H]N-methylspiperone. Although 1 was confirmed as D2R-preferential its selectivity binding functional studies lower previously reported. All to be D2R/D3R agonists GoBRET mitogenesis assays. Loss...
K(+) channels are differentially expressed throughout oligodendrocyte (Olg) development. K(V)1 family voltage-sensitive have been implicated in proliferation and migration of Olg progenitor cell (OPC) stage, inward rectifier K+ (K(IR))4.1 required for OPC differentiation to myelin-forming Olg. In this report we identified a Shaw channel, K(V)3.1, that is involved axon myelination. Application anti-K(V)3.1 antibody or knockout Kv3.1 gene decreased the sustained current component by 50% 75%,...
The dopamine D4 receptor (D4R) plays important roles in cognition, attention, and decision making. Novel D4R-selective ligands have promise medication development for neuropsychiatric conditions, including Alzheimer's disease substance use disorders. To identify new ligands, to understand the molecular determinants of agonist efficacy at D4R, we report a series eighteen novel based on classical D4R A-412997 (1, 2-(4-(pyridin-2-yl)piperidin-1-yl)- N-( m-tolyl)acetamide). Compounds were...
To identify novel D3 dopamine receptor (D3R) agonists, we conducted a high-throughput screen using β-arrestin recruitment assay. Counterscreening of the hit compounds provided an assessment their selectivity, efficacy, and potency. The most promising scaffold was optimized through medicinal chemistry resulting in enhanced potency selectivity. compound, ML417 (20), potently promotes D3R-mediated translocation, G protein activation, ERK1/2 phosphorylation (pERK) while lacking activity at other...
The effect of methoxy and hydroxy substitutions in different positions the phenoxy moiety N-((6,6-diphenyl-1,4-dioxan-2-yl)methyl)-2-phenoxyethan-1-amine scaffold on affinity/activity for D2-like, 5-HT1A, α1-adrenoceptor subtypes was evaluated. Multitarget compounds with suitable combinations dopaminergic serotoninergic profiles were discovered. In particular, 2-methoxy derivative 3 showed a multitarget combination 5-HT1A/D4 agonism D2/D3/5-HT2A antagonism, which may be favorable profile...
The improved chiral synthesis of the selective dopamine D3 receptor (D3R) antagonist (R)-N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3-hydroxybutyl)1H-indole-2-carboxamide ((R)-PG648) is described. same secondary alcohol intermediate was used to prepare enantiomers a 3-F-benzofuranyl analogue, BAK 2-66. absolute configurations 3-F were assigned from their X-ray crystal structures that confirmed retention configuration during fluorination with N,N-diethylaminosulfur trifluoride (DAST)....