scholarly journals A Review of the Updated Pharmacophore for the Alpha 5 GABA(A) Benzodiazepine Receptor Model

2015 ◽  
Vol 2015 ◽  
pp. 1-54 ◽  
Author(s):  
Terry Clayton ◽  
Michael M. Poe ◽  
Sundari Rallapalli ◽  
Poonam Biawat ◽  
Miroslav M. Savić ◽  
...  
Keyword(s):  
Structural Characteristics ◽  
Benzodiazepine Receptor ◽  
Binding Pocket ◽  
Positive Allosteric Modulator ◽  
Gaba A ◽  
Behavioral Studies ◽  
Selective Ligands ◽  
Recent Developments ◽  
Molecular Modeling Studies ◽  
Subtype Selective

An updated model of the GABA(A) benzodiazepine receptor pharmacophore of the α5-BzR/GABA(A) subtype has been constructed prompted by the synthesis of subtype selective ligands in light of the recent developments in both ligand synthesis, behavioral studies, and molecular modeling studies of the binding site itself. A number of BzR/GABA(A) α5 subtype selective compounds were synthesized, notably α5-subtype selective inverse agonist PWZ-029 (1) which is active in enhancing cognition in both rodents and primates. In addition, a chiral positive allosteric modulator (PAM), SH-053-2′F-R-CH3 (2), has been shown to reverse the deleterious effects in the MAM-model of schizophrenia as well as alleviate constriction in airway smooth muscle. Presented here is an updated model of the pharmacophore for α5β2γ2 Bz/GABA(A) receptors, including a rendering of PWZ-029 docked within the α5-binding pocket showing specific interactions of the molecule with the receptor. Differences in the included volume as compared to α1β2γ2, α2β2γ2, and α3β2γ2 will be illustrated for clarity. These new models enhance the ability to understand structural characteristics of ligands which act as agonists, antagonists, or inverse agonists at the Bz BS of GABA(A) receptors.

Novel N-Substituted Indol-3-ylglyoxylamides Probing the LDiand L1/L2Lipophilic Regions of the Benzodiazepine Receptor Site in Search for Subtype-Selective Ligands†

2007 ◽  
Vol 50 (7) ◽  
pp. 1627-1634 ◽  
Author(s):  
Giampaolo Primofiore ◽  
Sabrina Taliani ◽  
Federico Da Settimo ◽  
Anna Maria Marini ◽  
Concettina La Motta ◽  
...  
Keyword(s):  
Receptor Site ◽  
Benzodiazepine Receptor ◽  
Selective Ligands ◽  
Subtype Selective

scholarly journals Improved Synthesis of Anxiolytic, Anticonvulsant, and Antinociceptive α2/α3-GABA(A)-ergic Receptor Subtype Selective Ligands as Promising Agents to Treat Anxiety, Epilepsy, and Neuropathic Pain

Synthesis ◽  
2018 ◽  
Vol 50 (20) ◽  
pp. 4124-4132 ◽  
Author(s):  
James Cook ◽  
Guanguan Li ◽  
Lalit Golani ◽  
Rajwana Jahan ◽  
Farjana Rashid
Keyword(s):  
Neuropathic Pain ◽  
Column Chromatography ◽  
Good Yield ◽  
Receptor Subtype ◽  
Alternative Procedure ◽  
Gaba A ◽  
Selective Ligands ◽  
Purification Methods ◽  
Imine Reduction ◽  
Subtype Selective

An improved synthesis of the anxiolytic, anticonvulsant, and antinociceptive compounds: Hz-166, and its bioisosteres 1,2,4-oxadiazole (MP-III-080) and 1,3-oxazole (KRM-II-81) were synthesized in higher yields and with more facile purification methods (crystallization, etc.) in multigram quantities without column chromatography. In the synthesis of KRM-II-81, an alternative procedure was employed using the selective reducing reagent, potassium diisobutyl-tert-butoxyaluminum hydride (PDBBA), to prepare the desired C(3)-aldehyde in the absence of N(5)–C(6) imine reduction in good yield on a 20 gram scale.

The nature of the ligand-binding pocket of estrogen receptor alpha and beta: The search for subtype-selective ligands and implications for the prediction of estrogenic activity

2003 ◽  
Vol 75 (11-12) ◽  
pp. 2397-2403 ◽  
Author(s):  
J. A. Katzenellenbogen ◽  
R. Muthyala ◽  
B. S. Katzenellenbogen
Keyword(s):  
Estrogen Receptor ◽  
Ligand Binding ◽  
Estrogen Receptor Alpha ◽  
Estrogenic Activity ◽  
Binding Pocket ◽  
Receptor Alpha ◽  
Subtype Selectivity ◽  
Selective Ligands ◽  
Binding Pockets ◽  
Subtype Selective

The ligand-binding pockets of estrogen receptor alpha and beta (ERα and ERβ) appear to have subpockets of different size and flexibility. To find ligands that will discriminate between the two ER subtypes on the basis of affinity or efficacy, we have prepared compounds of varying size, shape and structure. We have evaluated the binding affinity of these compounds and their potency and efficacy as transcriptional activators through ERα and ERβ. In this manner, we have identified a number of ligands that show pronounced ER subtype selectivity. These studies also highlight the eclectic structure–activity relationships of estrogens and the challenges inherent in developing computational methods for the prediction of estrogenic activity.

scholarly journals Molecular Basis for the Subtype Discrimination of the Estrogen Receptor-β-Selective Ligand, Diarylpropionitrile

2003 ◽  
Vol 17 (2) ◽  
pp. 247-258 ◽  
Author(s):  
Jun Sun ◽  
Jerome Baudry ◽  
John A. Katzenellenbogen ◽  
Benita S. Katzenellenbogen
Keyword(s):  
Estrogen Receptor ◽  
Ligand Binding ◽  
Molecular Basis ◽  
Binding Pocket ◽  
Ligand Binding Pocket ◽  
Selective Ligand ◽  
Selective Ligands ◽  
Human Estrogen Receptor ◽  
Subtype Selective ◽  
Selective Character

Abstract Although the two subtypes of the human estrogen receptor (ER), ERα and ERβ, share only 56% amino acid sequence identity in their ligand binding domain (LBD), the residues that surround the ligand are nearly identical; nevertheless, subtype-selective ligands are known. To understand the molecular basis by which diarylpropionitrile (DPN), an ERβ-selective ligand, is able to discriminate between the two ERs, we examined its activity on ER mutants and chimeric constructs generated by DNA shuffling. The N-terminal region of the ERβ LBD (through helix 6) appears to be fully responsible for the ERβ selectivity of DPN. In fact, a single ERα point mutation (L384M) was largely sufficient to switch the DPN response of this ER to that of the ERβ type, but residues in helix 3 are also important in achieving the full ERβ selectivity of DPN. Using molecular modeling, we found an energetically favorable fit for the S-DPN enantiomer in ERβ, in which the proximal phenol mimics the A ring of estradiol, and the nitrile engages in stabilizing interactions with residues in the ligand-binding pocket of ERβ. Our findings highlight that a limited number of critical interactions of DPN with the ERβ ligand-binding pocket underlie its ER subtype-selective character.

scholarly journals Recent Developments in Inonotus obliquus (Chaga mushroom) Polysaccharides: Isolation, Structural Characteristics, Biological Activities and Application

Polymers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 1441
Author(s):  
Yangpeng Lu ◽  
Yanan Jia ◽  
Zihan Xue ◽  
Nannan Li ◽  
Junyu Liu ◽  
...  
Keyword(s):  
Biological Activities ◽  
Structural Characteristics ◽  
Potential Candidate ◽  
Health Food ◽  
Inonotus Obliquus ◽  
Recent Developments ◽  
Inonotus Obliquus Polysaccharide ◽  
Future Work

Inonotus obliquus (Chaga mushroom) is a kind of medicine and health food widely used by folk in China, Russia, Korea, and some occidental countries. Among the extracts from Inonotus obliquus, Inonotus obliquus polysaccharide (IOPS) is supposed to be one of the major bioactive components in Inonotus obliquus, which possesses antitumor, antioxidant, anti-virus, hypoglycemic, and hypolipidemic activities. In this review, the current advancements on extraction, purification, structural characteristics, and biological activities of IOPS were summarized. This review can provide significant insight into the IOPS bioactivities as their in vitro and in vivo data were summarized, and some possible mechanisms were listed. Furthermore, applications of IOPS were reviewed and discussed; IOPS might be a potential candidate for the treatment of cancers and type 2 diabetes. Besides, new perspectives for the future work of IOPS were also proposed.

scholarly journals Recent Developments of Antimony-Based Anodes for Sodium- and Potassium-Ion Batteries

2021 ◽  
Author(s):  
Bochao Chen ◽  
Ming Liang ◽  
Qingzhao Wu ◽  
Shan Zhu ◽  
Naiqin Zhao ◽  
...  
Keyword(s):  
Structural Characteristics ◽  
Low Cost ◽  
Potassium Ion ◽  
Research Progress ◽  
Research Directions ◽  
Weak Charge ◽  
Recent Developments ◽  
High Theoretical Capacity ◽  
Further Development ◽  
Sodium And Potassium

AbstractThe development of sodium-ion (SIBs) and potassium-ion batteries (PIBs) has increased rapidly because of the abundant resources and cost-effectiveness of Na and K. Antimony (Sb) plays an important role in SIBs and PIBs because of its high theoretical capacity, proper working voltage, and low cost. However, Sb-based anodes have the drawbacks of large volume changes and weak charge transfer during the charge and discharge processes, thus leading to poor cycling and rapid capacity decay. To address such drawbacks, many strategies and a variety of Sb-based materials have been developed in recent years. This review systematically introduces the recent research progress of a variety of Sb-based anodes for SIBs and PIBs from the perspective of composition selection, preparation technologies, structural characteristics, and energy storage behaviors. Moreover, corresponding examples are presented to illustrate the advantages or disadvantages of these anodes. Finally, we summarize the challenges of the development of Sb-based materials for Na/K-ion batteries and propose potential research directions for their further development.

scholarly journals AZD-3043

2012 ◽  
Vol 116 (6) ◽  
pp. 1267-1277 ◽  
Author(s):  
Talmage D. Egan ◽  
Shinju Obara ◽  
Thomas E. Jenkins ◽  
Sarah S. Jaw-Tsai ◽  
Shanti Amagasu ◽  
...  
Keyword(s):  
Dynamic Model ◽  
Metabolic Pathway ◽  
Liver Microsomes ◽  
Allosteric Modulator ◽  
Positive Allosteric Modulator ◽  
Duration Of Action ◽  
Chloride Currents ◽  
Gaba A ◽  
Hypnotic Agent

Background Propofol can be associated with delayed awakening after prolonged infusion. The aim of this study was to characterize the preclinical pharmacology of AZD-3043, a positive allosteric modulator of the γ-aminobutyric acid type A (GABA(A)) receptor containing a metabolically labile ester moiety. The authors postulated that its metabolic pathway would result in a short-acting clinical profile. Methods The effects of AZD-3043, propofol, and propanidid were studied on GABA(A) receptor-mediated chloride currents in embryonic rat cortical neurons. Radioligand binding studies were also performed. The in vitro stability of AZD-3043 in whole blood and liver microsomes was evaluated. The duration of the loss of righting reflex and effects on the electroencephalograph evoked by bolus or infusion intravenous administration were assessed in rats. A mixed-effects kinetic-dynamic model using minipigs permitted exploration of the clinical pharmacology of AZD-3043. Results AZD-3043 potentiated GABA(A) receptor-mediated chloride currents and inhibited [(35)S]tert-butylbicyclophosphorothionate binding to GABA(A) receptors. AZD-3043 was rapidly hydrolyzed in liver microsomes from humans and animals. AZD-3043 produced hypnosis and electroencephalograph depression in rats. Compared with propofol, AZD-3043 was shorter acting in rats and pigs. Computer simulation using the porcine kinetic-dynamic model demonstrated that AZD-3043 has very short 50 and 80% decrement times independent of infusion duration. Conclusions AZD-3043 is a positive allosteric modulator of the GABA(A) receptor in vitro and a sedative-hypnotic agent in vivo. The esterase dependent metabolic pathway results in rapid clearance and short duration of action even for long infusions. AZD-3043 may have clinical potential as a sedative-hypnotic agent with rapid and predictable recovery.

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