Development of Polar Adenosine A2A Receptor Agonists for Inflammatory Bowel Disease: Synergism with A2B Antagonists

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Discovery of BMS-753426: A Potent Orally Bioavailable Antagonist of CC Chemokine Receptor 2

To improve the metabolic stability profile of BMS-741672 (1a), we undertook a structure–activity relationship study in our trisubstituted cyclohexylamine series. This ultimately led to the identification of 2d (BMS-753426) as a potent and orally bioavailable antagonist of CCR2. Compared to previous clinical candidate 1a, the tert-butyl amine 2d showed significant improvements in pharmacokinetic properties, with lower clearance and higher oral bioavailability. Furthermore, compound 2d exhibited improved affinity for CCR5 and good activity in models of both monocyte migration and multiple sclerosis in the hCCR2 knock-in mouse. The synthesis of 2d was facilitated by the development of a simplified approach to key intermediate (4R)-9b that deployed a stereoselective reductive amination which may prove to be of general interest.     

Molecular Dynamics Simulation of Chemokine Receptors in Lipid Bilayer: A Case Study on C–C Chemokine Receptor Type 2

Chemokine receptors belong to the membrane proteins that are included in many physiological phenomena. However, the mechanism of their action is unknown at the atomistic level in different aspects. In this study, a computational pipeline is exploited to investigate the molecular basis of how the structure of C–C chemokine receptor type 2, a prototypical chemokine receptor, is affected by lipid bilayer and an antagonist (INCB3344). This study includes homology modeling, molecular dynamics simulation in lipid bilayer, and docking. A detailed mechanism of INCB3344 has been described. Tyr 49, Trp 98, Tyr 120, His 121, and Glu 291 are proved to play important roles in binding. Integrating results obtained in this study and experimental data help us to suggest a two‐step ligand‐binding mechanism. The N‐terminus of protein first sticks out from the extracellular domain suitable for the contact with the antagonist. Binding of ligand to this segment leads to the geometrical changes to facilitate the ligand interactions with extracellular loop 2 of C–C chemokine receptor type 2. Finally, the interactions occurring between extracellular loop 2 and ligand induce conformational changes in C–C chemokine receptor type 2 structure. These changes bring the ligand closer to the binding pocket, allowing the interaction between INCB3344 and the residues of active site.     

Triazole Appending Agent (TAAG): A New Synthon for Preparing Iodine-Based Molecular Imaging and Radiotherapy Agents

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Structure-Based Design of Reactive Nucleosides for Site-Specific Modification of the A2A Adenosine Receptor

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Discovery of Investigational Drug CT1812, an Antagonist of the Sigma-2 Receptor Complex for Alzheimer’s Disease

An unbiased phenotypic neuronal assay was developed to measure the synaptotoxic effects of soluble Aβ oligomers. A collection of CNS druglike small molecules prepared by conditioned extraction was screened. Compounds that prevented and reversed synaptotoxic effects of Aβ oligomers in neurons were discovered to bind to the sigma-2 receptor complex. Select development compounds displaced receptor-bound Aβ oligomers, rescued synapses, and restored cognitive function in transgenic hAPP Swe/Ldn mice. Our first-in-class orally administered small molecule investigational drug 7 (CT1812) has been advanced to Phase II clinical studies for Alzheimer’s disease.     

Synthesis,radiosynthesis and preliminary in vivo evaluation of [123I]‐(4‐fluorophenyl) {1‐[2‐(2‐iodophenyl)ethyl]piperidin‐4‐yl}methanone,a potential 5‐HT2A‐antagonist for SPECT brain imaging

Many people suffer from psychiatric illnesses like depression and anorexia. Relevant to these diseases is amongst others a malfunctioning of brain 5‐HT_2A‐receptors. To allow in vivo quantification of these receptors with Single Photon Emission Computerized Tomography (SPECT), a radiolabelled ligand with high 5‐HT_2A affinity is needed. This work reports the radiosynthesis of [¹²³I]‐(4‐fluorophenyl) {1‐[2‐(2‐iodophenyl)ethyl]piperidin‐4‐yl}methanone, the synthesis of its precursor, (4‐fluorophenyl) {1‐[2‐(2‐bromophenyl)ethyl]piperidin‐4‐yl}methanone, and the preliminary in vivo evaluation of the tracer. The precursor was synthesized with a total yield of 40%. Radiolabelling was performed using a halogen exchange reaction and the yield was 70%. Radiochemical purity was >95%, and specific activity was at least 2.4 Ci/µmol. Log P was measured to be 2.52. The tracer showed uptake in mice brain (3.5% I.D./g tissue at 3 min post injection) and therefore will be evaluated further by regional brain biodistribution and displacement studies in rabbits. Copyright © 2004 John Wiley & Sons, Ltd.     

Synthesis and in vivo evaluation in mice of [123I]‐(4‐fluorophenyl)[1‐(3‐iodophenethyl)piperidin‐4‐yl]methanone as a potential SPECT‐tracer for the serotonin 5‐HT2A receptor

This work reports the synthesis, radiolabelling and in vivo evaluation in NMRI mice of [¹²³I]‐(4‐fluorophenyl)[1‐(3‐iodophenethyl)piperidin‐4‐yl]methanone ([¹²³I]‐3‐I‐CO) as a potential SPECT tracer for the 5‐HT_2A receptor. The tributylstannylprecursor was synthesized with a 15% overall yield. Radiolabelling was performed using an electrophilic iododestannylation with yields of 85%. Radiochemical purity was always >95%. Log P was determined to be 3.10±0.10. The tracer showed good uptake in mouse brain (6.3±1.3% ID/g tissue at 10 min p.i., 2±0.36% ID/g tissue at 1 h p.i.). These results warrant further research in larger animals to determine suitability of [¹²³I]‐3‐I‐CO as a 5‐HT_2A tracer. Copyright © 2007 John Wiley & Sons, Ltd.     

Selective Blockade of Dopamine D3 Receptors Enhances while D2 Receptor Antagonism Impairs Social Novelty Discrimination and Novel Object Recognition in Rats: A Key Role for the Prefrontal Cortex

Dopamine D₃ receptor antagonists exert pro-cognitive effects in both rodents and primates. Accordingly, this study compared the roles of dopamine D₃ vs D₂ receptors in social novelty discrimination (SND), which relies on olfactory cues, and novel object recognition (NOR), a visual-recognition task. The dopamine D₃ receptor antagonist, {"type":"entrez-protein","attrs":{"text":"S33084","term_id":"420474","term_text":"pir||S33084"}}S33084 (0.04–0.63 mg/kg), caused a dose-related reversal of delay-dependent impairment in both SND and NOR procedures in adult rats. Furthermore, mice genetically deficient in dopamine D₃ receptors displayed enhanced discrimination in the SND task compared with wild-type controls. In contrast, acute treatment with the preferential dopamine D₂ receptor antagonist, L741,626 (0.16–5.0 mg/kg), or with the dopamine D₃ agonist, PD128,907 (0.63–40 μg/kg), caused a dose-related impairment in performance in rats in both tasks after a short inter-trial delay. Bilateral microinjection of {"type":"entrez-protein","attrs":{"text":"S33084","term_id":"420474","term_text":"pir||S33084"}}S33084 (2.5 μg/side) into the prefrontal cortex (PFC) of rats increased SND and caused a dose-related (0.63–2.5 μg/side) improvement in NOR, while intra-striatal injection (2.5 μg/side) had no effect on either. In contrast, bilateral microinjection of L741,626 into the PFC (but not striatum) caused a dose-related (0.63–2.5 μg/side) impairment of NOR. These observations suggest that blockade of dopamine D₃ receptors enhances both SND and NOR, whereas D₃ receptor activation or antagonism of dopamine D₂ receptor impairs cognition in these paradigms. Furthermore, these actions are mediated, at least partly, by the PFC. These data have important implications for exploitation of dopaminergic mechanisms in the treatment of schizophrenia and other CNS disorders, and support the potential therapeutic utility of dopamine D₃ receptor antagonism.     

Radiosynthesis of 11C-Levetiracetam: A Potential Marker for PET Imaging of SV2A Expression

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(R)-2-Phenylpyrrolidine Substituted Imidazopyridazines: A New Class of Potent and Selective Pan-TRK Inhibitors

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Potent,Long-Acting Cyclopentane-1,3-Dione Thromboxane (A2)-Receptor Antagonists

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Discovery of 3,4-Dihydropyrimidin-2(1H)-ones As a Novel Class of Potent and Selective A2B Adenosine Receptor Antagonists

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Virtual Screening of CB2 Receptor Agonists from Bayesian Network and High‐Throughput Docking: Structural Insights into Agonist‐Modulated GPCR Features

The relevance of CB₂‐mediated therapeutics is well established in the treatment of pain, neurodegenerative and gastrointestinal tract disorders. Recent works such as the crystallization of class‐A G‐protein‐coupled receptors in a range of active states and the identification of specific anchoring sites for CB₂ agonists challenged us to design a reliable agonist‐bound homology model of CB₂ receptor. Docking‐scoring enrichment tests of a high‐throughput virtual screening of 140 compounds led to 13 hits within the micromolar affinity range. Most of these hits behaved as CB₂ agonists, among which two novel full agonists emerged. Although the main challenge was a high‐throughput docking run targeting an agonist‐bound state of a CB₂ model, a prior 2D ligand‐based Bayesian network was computed to enrich the input commercial library for 3D screening. The exclusive discovery of agonists illustrates the reliability of this agonist‐bound state model for the identification of polar and aromatic amino acids as new agonist‐modulated CB₂ features to be integrated in the wide activation pathway of G‐protein‐coupled receptors.     

Discovery of TUG-770: A Highly Potent Free Fatty Acid Receptor 1 (FFA1/GPR40) Agonist for Treatment of Type 2 Diabetes

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Radiosynthesis and Biological Evaluation of [18F]R91150, a Selective 5-HT2A Receptor Antagonist for PET-Imaging

Serotonergic 5-HT_2A receptors in cortical and forebrain regions are an important substrate for the neuromodulatory actions of serotonin in the brain. They have been implicated in the etiology of many neuropsychiatric disorders and serve as a target for antipsychotic, antidepressant, and anxiolytic drugs. Positron emission tomography imaging using suitable radioligands can be applied for in vivo quantification of receptor densities and receptor occupancy for therapy evaluation. Recently, the radiosynthesis of the selective 5-HT_2AR antagonist [¹⁸F]{"type":"entrez-nucleotide","attrs":{"text":"R91150","term_id":"958690"}}R91150 was reported. However, the six-step radiosynthesis is cumbersome and time-consuming with low radiochemical yields (RCYs) of <5%. In this work, [¹⁸F]{"type":"entrez-nucleotide","attrs":{"text":"R91150","term_id":"958690"}}R91150 was prepared using late-stage Cu-mediated radiofluorination to simplify its synthesis. The detailed protocol enabled us to obtain RCYs of 14 ± 1%, and the total synthesis time was reduced to 60 min. In addition, autoradiographic studies with [¹⁸F]{"type":"entrez-nucleotide","attrs":{"text":"R91150","term_id":"958690"}}R91150 in rat brain slices revealed the typical uptake pattern of 5-HT_2A receptor ligands.     

Development of [123I]IPEB and [123I]IMPEB as SPECT Radioligands for Metabotropic Glutamate Receptor Subtype 5

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Design,Synthesis, and Evaluation of Tetrasubstituted Pyridines as Potent 5-HT2C Receptor Agonists

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Structure–Activity Relationship and Evaluation of Phenethylamine and Tryptamine Derivatives for Affinity towards 5-Hydroxytryptamine Type 2A Receptor

Among 14 subtypes of serotonin receptors (5-HTRs), 5-HT_2AR plays important roles in drug addiction and various psychiatric disorders. Agonists for 5-HT_2AR have been classified into three structural groups: phenethylamines, tryptamines, and ergolines. In this study, the structure-activity relationship (SAR) of phenethylamine and tryptamine derivatives for binding 5-HT_2AR was determined. In addition, functional and regulatory evaluation of selected compounds was conducted for extracellular signal-regulated kinases (ERKs) and receptor endocytosis. SAR studies showed that phenethylamines possessed higher affinity to 5-HT_2AR than tryptamines. In phenethylamines, two phenyl groups were attached to the carbon and nitrogen (R³) atoms of ethylamine, the backbone of phenethylamines. Alkyl or halogen groups on the phenyl ring attached to the β carbon exerted positive effects on the binding affinity when they were at para positions. Oxygen-containing groups attached to R³ exerted mixed influences depending on the position of their attachment. In tryptamine derivatives, tryptamine group was attached to the β carbon of ethylamine, and ally groups were attached to the nitrogen atom. Oxygen-containing substituents on large ring and alkyl substituents on the small ring of tryptamine groups exerted positive and negative influence on the affinity for 5-HT_2AR, respectively. Ally groups attached to the nitrogen atom of ethylamine exerted negative influences. Functional and regulatory activities of the tested compounds correlated with their affinity for 5-HT_2AR, suggesting their agonistic nature. In conclusion, this study provides information for designing novel ligands for 5-HT_2AR, which can be used to control psychiatric disorders and drug abuse.