scholarly journals Sulfonium Ligands of the α7 nAChR

Molecules ◽  
2021 ◽  
Vol 26 (18) ◽  
pp. 5643
Author(s):  
Nicole A. Horenstein ◽  
Clare Stokes ◽  
Roger L. Papke
Keyword(s):  
Partial Agonist ◽  
Receptor Subtype ◽  
Structural Element ◽  
Α7 Nicotinic Acetylcholine Receptor ◽  
Subtype Selectivity ◽  
Α7 Nachr ◽  
Wide Range ◽  
Further Development ◽  
Pi Interactions ◽  
Positively Charged

The α7 nicotinic acetylcholine receptor (nAChR) is an important target given its role in cognitive function as well as in the cholinergic anti-inflammatory pathway, where ligands that are effective at stabilizing desensitized states of the receptor are of particular interest. The typical structural element associated with a good desensitizer is the ammonium pharmacophore, but recent work has identified that a trivalent sulfur, in the positively charged sulfonium form, can substitute for the nitrogen in the ammonium pharmacophore. However, the breadth and scope of employing the sulfonium group is largely unexplored. In this work, we have surveyed a disparate group of sulfonium compounds for their functional activity with α7 as well as other nAChR subtypes. Amongst them, we found that there is a wide range of ability to induce α7 desensitization, with 4-hydroxyphenyldimethylsulfonium and suplatast sulfonium salts being the most desensitizing. The smallest sulfonium compound, trimethylsulfonium, was a partial agonist for α7 and other neuronal nAChR. Molecular docking into the α7 receptor extracellular domain revealed preferred poses in the orthosteric binding site for all but one compound, with typical cation–pi interactions as seen with traditional ammonium compounds. A number of the compounds tested may serve as useful platforms for further development of α7 desensitizing ability and for receptor subtype selectivity.

scholarly journals Assessment of select synthetic cannabinoid receptor agonist bias and selectivity between the type 1 and type 2 cannabinoid receptor

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ayat Zagzoog ◽  
Asher L. Brandt ◽  
Tallan Black ◽  
Eunhyun D. Kim ◽  
Riley Burkart ◽  
...  
Keyword(s):  
Cannabinoid Receptors ◽  
Cannabinoid Receptor ◽  
Partial Agonist ◽  
Synthetic Cannabinoid ◽  
Receptor Subtype ◽  
Service Agency ◽  
Subtype Selectivity ◽  
Insight Into

AbstractThe first synthetic cannabinoid receptor agonists (SCRAs) were designed as tool compounds to study the endocannabinoid system’s two predominant cannabinoid receptors, CB1R and CB2R. Unfortunately, novel SCRAs now represent the most rapidly proliferating novel psychoactive substances (NPS) of abuse globally. Unlike ∆9-tetrahydrocannabinol, the CB1R and CB2R partial agonist and the intoxicating constituent of Cannabis, many SCRAs characterized to date are full agonists of CB1R. Gaining additional insight into the pharmacological activity of these SCRAs is critical to assess and regulate NPSs as they enter the marketplace. The purpose of this study was to assess select SCRAs recently identified by Canadian police, border service agency, private companies and the illicit market as potential CB1R and CB2R agonists. To this end, fifteen SCRAs were screened for in vitro activity and in silico interactions at CB1R and CB2R. Several SCRAs were identified as being highly biased for cAMP inhibition or βarrestin2 recruitment and receptor subtype selectivity between CB1R and CB2R. The indazole ring and halogen-substituted butyl or pentyl moieties were identified as two structural features that may direct βarrestin2 bias. Two highly-biased SCRAs—JWH-018 2′-napthyl-N-(3-methylbutyl) isomer (biased toward cAMP inhibition) and 4-fluoro MDMB-BINACA (biased toward βarrestin2 recruitment) displayed unique and differential in vivo activity in mice. These data provide initial insight into the correlations between structure, signalling bias, and in vivo activity of the SCRAs.

scholarly journals PET Brain imaging of α7-nAChR with [18F]ASEM

2018 ◽  
Author(s):  
Dean F. Wong ◽  
Hiroto Kuwabara ◽  
Andrew G. Horti ◽  
Joshua M. Roberts ◽  
Ayon Nandi ◽  
...  
Keyword(s):  
Healthy Volunteers ◽  
Partial Agonist ◽  
Plasma Concentrations ◽  
Cingulate Cortex ◽  
Affinity Constant ◽  
Normal Brain ◽  
Α7 Nicotinic Acetylcholine Receptor ◽  
Brain Physiology ◽  
Α7 Nachr

AbstractThe α7 nicotinic acetylcholine receptor (nAChR) increasingly has been implicated in normal brain physiology, as well as in neuropsychiatric disorders. The a7-nAChR primarily is located in cerebral cortex and sub-cortical regions, compared to the α4β2 nAChR subtype that has a more subcortical distribution. The highly cortical distribution suggests a role of a7-nAChR in cognition. We expanded the first-in-human PET imaging of α7-nAChR with [18F]ASEM from five to 21 healthy non-smoking volunteers and added preliminary evidence of binding in six male patients with schizophrenia. Study aims included 1) confirmation of test-retest reproducibility of [18F]ASEM binding in normal volunteers, 2) demonstration of specificity of [18F]ASEM binding by competition with DMXB-A, an α7-nAChR partial agonist previously tested in clinical trials of patients with schizophrenia, 3) estimation of [18F]ASEM binding potentials and α7-nAChR density in vivo in humans, and 4) α7-nAChR binding in patients with schizophrenia compared to healthy volunteers.Test-retest PET confirmed reproducibility (>90%) (variability ≤ 7%) of [18F]ASEM volume of distribution (Vt) estimates in healthy volunteers. Repeated sessions of PET in five healthy subjects included baseline and effect of inhibition after oral administration of 150 mg DMXB-A. From reduction of binding potentials, we estimated the dose-dependent occupancy of α7-nAChR by DMXB-A at 17-49% for plasma concentrations at 60-200 nM DMXB-A. In agreement with evidence post-mortem, α7-nAChR density (Bmax) averaged 0.67-0.82 nM and inhibitor affinity constant (Ki) averaged 170-385 nM. Median Vt in a feasibility study of six patients with schizophrenia was lower than in healthy volunteers in cingulate cortex, frontal cortex, and hippocampus. Mann-Whitney test identified cingulate cortex and hippocampus as regions with significantly lower median Vt in patients than in healthy volunteers when a single outlier patient was excluded from analysis (P = 0.02, corrected for multiple comparisons).

Application of TEM to Deformation, Wear, and Fracture of Ceramics

1974 ◽  
Vol 32 ◽  
pp. 472-473
Author(s):  
B. J. Hockey
Keyword(s):  
Wear Resistance ◽  
High Temperature ◽  
Mechanical Behavior ◽  
Brittle Materials ◽  
High Temperature Strength ◽  
Wide Range ◽  
Corrosive Environments ◽  
Further Development

Ceramics, such as Al2O3 and SiC have numerous current and potential uses in applications where high temperature strength, hardness, and wear resistance are required often in corrosive environments. These materials are, however, highly anisotropic and brittle, so that their mechanical behavior is often unpredictable. The further development of these materials will require a better understanding of the basic mechanisms controlling deformation, wear, and fracture.The purpose of this talk is to describe applications of TEM to the study of the deformation, wear, and fracture of Al2O3. Similar studies are currently being conducted on SiC and the techniques involved should be applicable to a wide range of hard, brittle materials.

scholarly journals Natural Polyhydroxy Flavonoids, Curcuminoids, and Synthetic Curcumin Analogs as α7 nAChRs Positive Allosteric Modulators

2021 ◽  
Vol 22 (2) ◽  
pp. 973
Author(s):  
Marta Ximenis ◽  
José Mulet ◽  
Salvador Sala ◽  
Francisco Sala ◽  
Manuel Criado ◽  
...  
Keyword(s):  
Biological Evaluation ◽  
Allosteric Modulators ◽  
Α7 Nicotinic Acetylcholine Receptor ◽  
Curcumin Analogues ◽  
Curcumin Derivatives ◽  
Curcumin Analogs ◽  
Naturally Occurring ◽  
Α7 Nachr ◽  
Positive Allosteric Modulators ◽  
Α7 Nachrs

The α7 nicotinic acetylcholine receptor (α7 nAChR) is a ligand-gated ion channel that is involved in cognition disorders, schizophrenia, pain, and inflammation. Allosteric modulation of this receptor might be advantageous to reduce the toxicity in comparison with full agonists. Our previous results obtained with some hydroxy-chalcones, which were identified as positive allosteric modulators (PAMs) of α7 nAChR, prompted us to evaluate the potential of some structurally related naturally occurring flavonoids and curcuminoids and some synthetic curcumin analogues, with the aim of identifying new allosteric modulators of the α7 nAChR. Biological evaluation showed that phloretin, demethoxycurcumin, and bis-demethoxicurcuming behave as PAMs of α7 nAChR. In addition, some new curcumin derivatives were able to enhance the signal evoked by ACh; the activity values found for the tetrahydrocurcuminoid analog 23 were especially promising.

Modulation of PPAR receptor subtype selectivity of the ligands: Aliphatic chain vs aromatic ring as a spacer between pharmacophore and the lipophilic moiety

2008 ◽  
Vol 18 (24) ◽  
pp. 6471-6475 ◽  
Author(s):  
Harikishore Pingali ◽  
Mukul Jain ◽  
Shailesh Shah ◽  
Pravin Patil ◽  
Pankaj Makadia ◽  
...  
Keyword(s):  
Aromatic Ring ◽  
Receptor Subtype ◽  
Aliphatic Chain ◽  
Subtype Selectivity

APN1125: A clinical stage α7 nicotinic acetylcholine receptor partial agonist

2015 ◽  
Vol 97 (4) ◽  
pp. 636 ◽  
Author(s):  
Gerald Koelsch ◽  
Michael J. Detke ◽  
Karen E. Stevens ◽  
Leonard T. Meltzer ◽  
Alvin V. Terry ◽  
...  
Keyword(s):  
Acetylcholine Receptor ◽  
Nicotinic Acetylcholine Receptor ◽  
Partial Agonist ◽  
Clinical Stage ◽  
Α7 Nicotinic Acetylcholine Receptor ◽  
Nicotinic Acetylcholine

scholarly journals The neuroprotective effects of activated α7 nicotinic acetylcholine receptor against mutant copper–zinc superoxide dismutase 1-mediated toxicity

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Taisei Ito ◽  
Masatoshi Inden ◽  
Tomoyuki Ueda ◽  
Yuta Asaka ◽  
Hisaka Kurita ◽  
...  
Keyword(s):  
Superoxide Dismutase ◽  
Motor Neurons ◽  
Superoxide Dismutase 1 ◽  
Α7 Nicotinic Acetylcholine Receptor ◽  
Neuroprotective Effects ◽  
Nicotinic Acetylcholine ◽  
Copper Zinc Superoxide Dismutase ◽  
Zinc Superoxide Dismutase ◽  
Α7 Nachr ◽  
Copper Zinc

AbstractAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the selective and progressive loss of motor neurons. Although many drugs have entered clinical trials, few have shown effectiveness in the treatment of ALS. Other studies have shown that the stimulation of α7 nicotinic acetylcholine receptor (nAChR) can have neuroprotective effects in some models of neurodegenerative disease, as well as prevent glutamate-induced motor neuronal death. However, the effect of α7 nAChR agonists on ALS-associated mutant copper–zinc superoxide dismutase 1 (SOD1) aggregates in motor neurons remains unclear. In the present study, we examined whether α7 nAChR activation had a neuroprotective effect against SOD1G85R-induced toxicity in a cellular model for ALS. We found that α7 nAChR activation by PNU282987, a selective agonist of α7 nAChR, exhibited significant neuroprotective effects against SOD1G85R-induced toxicity via the reduction of intracellular protein aggregates. This reduction also correlated with the activation of autophagy through the AMP-activated protein kinase (AMPK)–mammalian target of rapamycin (mTOR) signaling pathway. Furthermore, the activation of α7 nAChRs was found to increase the biogenesis of lysosomes by inducing translocation of the transcription factor EB (TFEB) into the nucleus. These results support the therapeutic potential of α7 nAChR activation in diseases that are characterized by SOD1G85R aggregates, such as ALS.

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