Synthesis and Preliminary Pharmacological Evaluation of 4′-Arylalkyl Analogues of Clozapine. IV. The Effects of Aromaticity and Isosteric Replacement

2008 ◽  
Vol 61 (12) ◽  
pp. 930 ◽  
Author(s):  
Ben Capuano ◽  
Ian T. Crosby ◽  
Edward J. Lloyd ◽  
Anna Podloucka ◽  
David A. Taylor
Keyword(s):  
Receptor Binding ◽  
Pharmacological Activity ◽  
Structural Characterization ◽  
Structural Model ◽  
Antipsychotic Agents ◽  
Pharmacological Effects ◽  
Aryl Group ◽  
Preliminary Results ◽  
Pharmacological Evaluation

We report the synthesis and preliminary pharmacological activity of a new series of tricyclic analogues of clozapine as potential antipsychotic agents for the treatment of schizophrenia. These compounds were designed based on a revised structural model, and investigate the length and nature of a designated linker (alkyl and alkyloxy) and the nature of the introduced aryl group (aromatic and heteroaromatic). The chemistry and structural characterization of this series of 4′-arylalkyl(oxy) analogues of clozapine are described. Preliminary results on the pharmacological effects of the selected linkers and introduced aryl groups on affinity for dopamine D4 and serotonin 5-HT2A receptors are discussed. Psychosis-related animal behavioural data for promising compounds identified from the receptor binding screen are also presented.

The Synthesis and Preliminary Pharmacological Evaluation of a Series of Substituted 4'-Phenoxypropyl Analogues of the Atypical Antipsychotic Clozapine

2010 ◽  
Vol 63 (1) ◽  
pp. 116 ◽  
Author(s):  
Ben Capuano ◽  
Ian T. Crosby ◽  
Fiona M. McRobb ◽  
Anna Podloucka ◽  
David A. Taylor ◽  
...  
Keyword(s):  
Receptor Binding ◽  
Antipsychotic Agents ◽  
Pharmacological Effects ◽  
Lead Compound ◽  
Substituted Phenols ◽  
Biochemical Effects ◽  
Primary Focus

Herein we report the synthesis, characterization, and preliminary pharmacological activity of a new series of substituted 4′-phenoxypropyl tricyclic analogues of clozapine as potential antipsychotic agents for the treatment of schizophrenia. The lead compound (3) for this investigation was designed based on a revised model derived from the structural hybridization of the commercial therapeutics clozapine (1) and haloperidol (2). The compounds described in this paper probe the biochemical effects of introducing a variety of electron-withdrawing and electron-donating substituents with the primary focus on the para-position of the introduced distal aromatic ring. The target compounds were readily prepared in three steps using the key intermediate lactam (8-chloro-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepine-11-one, 9), piperazine and commercially available substituted phenols. The chemistry and structural characterization of this series of substituted 4′-phenoxypropyl analogues of clozapine are described. Preliminary in vitro results on the pharmacological effects of the ring substituents on affinity for dopamine D4 and serotonin 5-HT2A receptors are discussed. Psychosis-related in vivo animal behavioural data for compounds identified with potential from the receptor binding screen are also presented.

Framework Stoichiometry and Electrical Conductivity of Si-Ge Based Structure-I Clathrates

2000 ◽  
Vol 626 ◽  
Author(s):  
Ganesh K. Ramachandran ◽  
Paul F. McMillan ◽  
Jianjun Dong ◽  
Jan Gryko ◽  
Otto F. Sankey
Keyword(s):  
Electrical Conductivity ◽  
Thermal Decomposition ◽  
Electronic Properties ◽  
Lattice Constant ◽  
Structural Characterization ◽  
Periodic Table ◽  
Preliminary Results ◽  
Tetrahedral Sites ◽  
Semiconducting Behavior

ABSTRACTWe report the synthesis and structural characterization of two Structure I clathrates in the KSi and Rb-Si systems. The alkali-Si clathrates are fully stoichiometric at the framework sites, i.e., devoid of framework vacancies. This is in sharp contrast to the analogous K-Ge, Rb-Ge and Rb-Sn, Cs-Sn systems, where vacancies are formed at one-third of the crystallographic 6c tetrahedral sites. This is rationalized in terms of Zintl-Klemm rules to remove the tetrahedral atom of its hypervalency. The contrasting behavior is understood in terms of weaker Tt-Tt (Tt – tetrelide, Si, Ge, Sn) bonding as one descends the periodic table, and results in poorly metallic conductivities for vacancy-free K7Si46 and Rb6Si46, but semiconducting behavior of K8Ge44. The observation suggests tuning of the electronic properties of Tt clathrates by substitution of (Si,Ge,Sn) on framework sites, for thermoelectric applications. We describe preliminary results designed to synthesize “mixed” Si-Ge clathrate structures. Thermal decomposition of K2SiGe results in formation of a Structure I clathrate with mixing of Si and Ge on framework sites. The lattice constant ao = 10.523(6) Å, is intermediate between those of K8Si46 and K8Ge44.

scholarly journals Structural characterization of ice XIX as the second polymorph related to ice VI

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Tobias M. Gasser ◽  
Alexander V. Thoeny ◽  
A. Dominic Fortes ◽  
Thomas Loerting
Keyword(s):  
High Resolution ◽  
Structural Characterization ◽  
Structural Model ◽  
Neutron Powder Diffraction ◽  
Ex Situ ◽  
Nucleation Kinetics ◽  
Icy Moons ◽  
First Order ◽  
Wide Range

AbstractIce polymorphs usually appear as hydrogen disorder-order pairs. Ice VI has a wide range of thermodynamic stability and exists in the interior of Earth and icy moons. Our previous work suggested ice β-XV as a second polymorph deriving from disordered ice VI, in addition to ice XV. Here we report thermal and structural characterization of the previously inaccessible deuterated polymorph using ex situ calorimetry and high-resolution neutron powder diffraction. Ice β-XV, now called ice XIX, is shown to be partially antiferroelectrically ordered and crystallising in a √2×√2×1 supercell. Our powder data recorded at subambient pressure fit best to the structural model in space group $$P\bar 4$$ P 4 ¯ . Key to the synthesis of deuterated ice XIX is the use of a DCl-doped D2O/H2O mixture, where the small H2O fraction enhances ice XIX nucleation kinetics. In addition, we observe the transition from ice XIX to its sibling ice XV upon heating, which proceeds via a transition state (ice VI‡) containing a disordered H-sublattice. To the best of our knowledge this represents the first order-order transition known in ice physics.

Abstract 307: Structural Characterization of Calcineurin A-Calsarcin 1 Assembly

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Carlos R Koscky Paier ◽  
Alisson C Cardoso ◽  
Tatiani L Brenneli ◽  
Rodrigo V Honorato ◽  
Fábio C Gozzo ◽  
...  
Keyword(s):  
Structural Characterization ◽  
Molecular Mechanisms ◽  
Structural Model ◽  
Mutational Analysis ◽  
Structural Similarity ◽  
Dynamics Simulation ◽  
Allosteric Site ◽  
In Silico Docking ◽  
Close Proximity

Signaling by the calcium-dependent phosphatase calcineurin (Cn) plays key roles in regulating cardiac development, hypertrophy, and pathological remodeling. Cn binds to and is negatively regulated by calsarcins (CS), a family of muscle-specific proteins. However, the molecular mechanisms involved in the inhibition of Cn by CS remain unclear. Understanding the architecture and structure of Cn-CS complex is critical to unravel the regulation of Cn by CS. Here we combined biochemical assays, chemical cross-linking coupled to mass spectrometry experiments (MS/MS), mutational analysis and a modeling strategy for structural characterization of CnA-CS1 assembly. The MS/MS data obtained from the cross-linked peptides of both proteins were used to guide an in silico docking of their polypeptide models. The protein complex models with the smallest estimated binding energy were clustered according to structural similarity and submitted to molecular dynamics simulation. The interacting surface of CnA was mapped in a pocket between the 1st and 3rd α-helixes and surrounding loops, while the corresponding surface of CS1 was mapped to the carboxyterminal loops within the Leu179-Phe185, Phe195-Ser199 and Thr250-Leu264 regions. Notably, the region of CnA that interacts with CS1 was found to be located in close proximity, but not coincident, to the β-sheet 14, the main binding site for the PxIxIT sequence of NFAT. Experiments performed with several CnA (FLAG-CnA) and CS1 (myc-CS1) mutants were used to validate the structural model of the CnA-CS1 assembly. The Lys40 (CnA) and Glu254 (CS1) residues were identified as critical for the complex stability. The model that emerges from this study supports the notion that CS1 interacts with an allosteric site to inhibit the activity of CnA. Alternatively, the close proximity of the CS1 to NFAT interacting site supports an interference of CS1 on the ability of CnA to bind and activate NFAT.

scholarly journals Isolation and structural characterization of insulin and glucagon from the holocephalan species Callorhynchus milii (elephantfish)

1989 ◽  
Vol 263 (1) ◽  
pp. 261-266 ◽  
Author(s):  
B C Berks ◽  
C J Marshall ◽  
A Carne ◽  
S M Galloway ◽  
J F Cutfield
Keyword(s):  
Gas Phase ◽  
Receptor Binding ◽  
Structural Characterization ◽  
Sequence Similarity ◽  
Cartilaginous Fish ◽  
Proteolytic Processing ◽  
Reverse Phase ◽  
High Sequence Similarity ◽  
Processing Mechanisms

Both insulin and glucagon from the pancreas of the holocephalan cartilaginous fish Callorhynchus milii (elephantfish) have been isolated and purified. Two reverse-phase h.p.l.c. steps enabled recovery of sufficient material for gas-phase sequencing of the intact chains as well as peptide digestion products. The elephantfish insulin sequence shows 14 differences from pig insulin, including two unusual substitutions, Val-A14 and Gln-B30, though none of these is thought likely to influence receptor binding significantly. The insulin B-chain contains 31 residues, one more than mammalian insulins, but markedly less than that of the closely related ratfish with which it otherwise exhibits high sequence similarity. Elephantfish and pig glucagons differ at only four positions, but there are six changes from the ratfish glucagon-36 (normal glucagon contains 29 residues) sequence. It is apparent that different prohormone proteolytic processing mechanisms operate in the two holocephalan species.

scholarly journals Structural Characterization of N‐Linked Glycans in the Receptor Binding Domain of the SARS‐CoV‐2 Spike Protein and their Interactions with Human Lectins

2020 ◽  
Vol 132 (52) ◽  
pp. 23971-23979 ◽  
Author(s):  
Maria Pia Lenza ◽  
Iker Oyenarte ◽  
Tammo Diercks ◽  
Jon Imanol Quintana ◽  
Ana Gimeno ◽  
...  
Keyword(s):  
Receptor Binding ◽  
Structural Characterization ◽  
Binding Domain ◽  
Spike Protein ◽  
Receptor Binding Domain

Aminimides as Potential CNS Acting Agents. II Design, Synthesis, and Receptor Binding of 4′-Arylalkyl Aminimide Analogues of Clozapine as Prospective Novel Antipsychotics

2008 ◽  
Vol 61 (1) ◽  
pp. 5 ◽  
Author(s):  
Ben Capuano ◽  
Ian T. Crosby ◽  
Edward J. Lloyd ◽  
Juliette E. Neve ◽  
David A. Taylor
Keyword(s):  
Atypical Antipsychotic ◽  
Receptor Binding ◽  
Structural Characterization ◽  
Marked Reduction ◽  
Second Generation ◽  
Functional Group ◽  
Design Synthesis ◽  
Biochemical Effects ◽  
Antipsychotic Activity

We report the synthesis of a series of second generation aminimide-based analogues of clozapine, investigating the length of the linker between the aminimide functional group and the introduced aryl moiety. The chemistry and structural characterization of this series of 4′-arylalkyl aminimide analogues of clozapine are described. Preliminary findings on the biochemical effects of linker length and type of aryl moiety on affinity for dopamine D4 and serotonin 5-HT2A receptors are discussed. All of the compounds showed a marked reduction in binding at the two receptors when compared with clozapine, thus showing a reduced potential for atypical antipsychotic activity.

Synthesis and Preliminary Pharmacological Evaluation of 4´-Arylmethyl Analogues of Clozapine. I. The Effect of Aromatic Substituents

2002 ◽  
Vol 55 (9) ◽  
pp. 565 ◽  
Author(s):  
B. Capuano ◽  
I. T. Crosby ◽  
E. J. Lloyd ◽  
D. A. Taylor
Keyword(s):  
Chemical Synthesis ◽  
Atypical Antipsychotic ◽  
Receptor Binding ◽  
Structural Characterization ◽  
Research Program ◽  
Structural Modification ◽  
Antagonist Activity ◽  
Pharmacological Evaluation ◽  
Binding Data ◽  
Positional Effects

As part of a research program to develop compounds with mixed dopamine D4 and serotonin 5-HT2A antagonist activity with potential for the treatment of schizophrenia, we report a family of compounds based on structural modification of the atypical antipsychotic, clozapine (2). The chemical synthesis, structural characterization and pharmacological evaluation of a series 4�-arylmethyl analogues of clozapine are described. Preliminary receptor binding data are presented, examining primarily the electronic and positional effects of substituents on the introduced arylmethyl group, and secondarily the nature of the aryl ring.

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