scholarly journals Crystallographic approach to determination of active conformations of LCAPs

2014 ◽  
Vol 70 (a1) ◽  
pp. C1697-C1697
Author(s):  
Marek Glowka ◽  
Malgorzata Szczesio ◽  
Andrzej Olczak
Keyword(s):  
Serotonin Receptor ◽  
Antidepressant Drugs ◽  
Terminal Group ◽  
Aliphatic Chain ◽  
Receptor Ligands ◽  
Piperazine Ring ◽  
Flexible Spacer ◽  
Or Groups ◽  
Conformational Freedom

Long-Chain Aryl-Piperazines (LCAPs) are well known serotonin receptor ligands used in several marketed antidepressant drugs. LCAPs consist of three structural units: a terminal group, an arylpiperazine at one N atom and an aliphatic chain (spacer) at the other N atom joining the two former units. Both the arylpiperazine and the terminal groups have rather rigid structures and thus their conformational freedom is limited. The opposite is true for the aliphatic spacer, which allows practically any orientation of the terminal group. The resulting diversity of conformations observed in the crystals of LCAPs is significant, which explains their affinity to many serotonin receptors. There is a vast literature on the subject and some qualitative observations were developed. However, due to the flexible spacer and diversity of the terminal groups, their usefulness is limited. Our X-ray (16 crystal structures) and affinity studies on almost sixty new LCAPs [1], together with the data from CSD, enable us to determine the common conformations of LCAPs and the relationships between structure, affinity and conformation. In the analysis, the following features were considered: (i) - axial/equatorial orientations of the substituents of the piperazine ring; (ii) –N1 protonation possible in the physiological environment; (iii) - a twist of the aryl ring; (iv) –the parity and the number of atoms in the spacer; (v) – the presence of heteroatoms or groups in the spacer; (vi) – the spatial position of the terminal group in relation to the piperazine ring.

scholarly journals Low Basicity as a Characteristic for Atypical Ligands of Serotonin Receptor 5-HT2

2021 ◽  
Vol 22 (3) ◽  
pp. 1035
Author(s):  
Sabina Podlewska ◽  
Ryszard Bugno ◽  
Enza Lacivita ◽  
Marcello Leopoldo ◽  
Andrzej J. Bojarski ◽  
...  
Keyword(s):  
Serotonin Receptors ◽  
Drug Targets ◽  
Serotonin Receptor ◽  
Transmembrane Helix ◽  
In Silico Analysis ◽  
Protonated Form ◽  
Receptor Ligands ◽  
Receptor System ◽  
Native Proteins

Serotonin receptors are extensively examined by academic and industrial researchers, due to their vital roles, which they play in the organism and constituting therefore important drug targets. Up to very recently, it was assumed that the basic nitrogen in compound structure is a necessary component to make it active within this receptor system. Such nitrogen interacts in its protonated form with the aspartic acid from the third transmembrane helix (D3x32) forming a hydrogen bond tightly fitting the ligand in the protein binding site. However, there are several recent studies that report strong serotonin receptor affinity also for compounds without a basic moiety in their structures. In the study, we carried out a comprehensive in silico analysis of the low-basicity phenomenon of the selected serotonin receptor ligands. We focused on the crystallized representatives of the proteins of 5-HT1B, 5-HT2A, 5-HT2B, and 5-HT2C receptors, and examined the problem both from the ligand- and structure-based perspectives. The study was performed for the native proteins, and for D3x32A mutants. The investigation resulted in the determination of nonstandard structural requirements for activity towards serotonin receptors, which can be used in the design of new nonbasic ligands.

Spacer conformation in biologically active molecules

2004 ◽  
Vol 76 (5) ◽  
pp. 959-964 ◽  
Author(s):  
J. Karolak-Wojciechowska ◽  
A. Fruzinski
Keyword(s):  
Statistical Data ◽  
Population Analysis ◽  
Cambridge Structural Database ◽  
Biologically Active ◽  
Aliphatic Chain ◽  
X Ray ◽  
Flexible Spacer ◽  
Conformational Preferences ◽  
Structural Database ◽  
The One

Based on our contemporary studies on the structures of biologically active molecules, we focus our attention on the aliphatic chain and its conformation. That flexible spacer definitely influenced the balanced position of all pharmacophoric points in molecules of biological ligands. The one atomic linker and two or three atomic spacers with one heteroatom X =O, S, CH2, NH have been taken into account. The conformational preferences clearly depend on the heteroatom X. In the discussion, we utilize our own X-ray data, computation chemistry methods, population analysis, and statistical data from the Cambridge Structural Database (CSD).

scholarly journals FORENSIC CASES IN THE NORTH OF CHILE: DETERMINATION OF ANTIDEPRESSANT DRUGS IN HUMAN WHOLE BLOOD

2013 ◽  
Vol 58 (2) ◽  
pp. 1733-1736 ◽  
Author(s):  
FELIPE BRAVO ◽  
CARMEN ZAMBRA ◽  
KARINA VENEGAS ◽  
DAVID RIOS ◽  
PEDRO BUC CALDERON ◽  
...  
Keyword(s):  
Whole Blood ◽  
Antidepressant Drugs ◽  
Human Whole Blood ◽  
The North

scholarly journals A glucan from active dry baker’s yeast (Saccharomyces cerevisiae): A chemical and enzymatic investigation of the structure

2003 ◽  
Vol 68 (11) ◽  
pp. 805-809 ◽  
Author(s):  
Dragan Zlatkovic ◽  
Dragica Jakovljevic ◽  
Djordje Zekovic ◽  
Miroslav Vrvic
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Optical Rotation ◽  
Linear Chain ◽  
Periodate Oxidation ◽  
Methylation Analysis ◽  
Yeast Saccharomyces Cerevisiae ◽  
New Approach ◽  
Main Structural Feature ◽  
Or Groups

The structure of a polysaccharide consisting of D-glucose isolated from the cell-wall of active dry baker?s yeast (Saccharomyces cerevisiae) was investigated by using methylation analysis, periodate oxidation, mass spectrometry, NMR spectroscopy, and enzymic hydrolysis, as a new approach in determination of structures. The main structural feature of the polysaccharide deduced on the basis of the obtained results is a linear chain of (1?3)-linked ?-D-glucopyranoses, a part of which is substituted through the positions O-6. The side units or groups are either a single D-glucopyranose or (1?3)-?-oligoglucosides, linked to the main chaing through (1?6)-glucosidic linkages. The low optical rotation as well as the 13C-NMR and FTIR spectra suggest that the glycosidic linkages are in the ?-D-configuration.

1,2,3,4-Tetrahydrocarbazoles as 5-HT6 Serotonin Receptor Ligands.

ChemInform ◽  
2004 ◽  
Vol 35 (31) ◽  
Author(s):  
Jean Chang-Fong ◽  
Jagadeesh B. Rangisetty ◽  
Malgorzata Dukat ◽  
Vincent Setola ◽  
Thomas Raffay ◽  
...  
Keyword(s):  
Serotonin Receptor ◽  
Receptor Ligands

Analytical Methods in Rubber Chemistry, Part I. General Analytical Considerations

1941 ◽  
Vol 14 (3) ◽  
pp. 628-640 ◽  
Author(s):  
E. H. Farmer
Keyword(s):  
Average Chain Length ◽  
Complex Molecules ◽  
Analytical Technique ◽  
Or Groups ◽  
Hydrocarbon Chains ◽  
Infinite Degree ◽  
Degree Of Degradation ◽  
Ethereal Oxygen ◽  
Made In

Abstract One of the consequences of the high-molecular character of rubber is the smallness of the effect on ultimate quantitative analysis of the presence of one or even several heteroatoms or groups in the long hydrocarbon chains. With rubber molecules possessing an average chain-length of about 4,500 isoprene units, the association of, say, ten nitrogen atoms wtih each chain would provide a nitrogen content of only about 0.0007 per cent, and the incorporation of about 0.005 per cent of ethereal oxygen in pure rubber hydrocarbon would be theoretically capable of providing sufficient linking material for an infinite degree of hetero-polymerization, or, if the oxygen were applied instead to produce the maximum possible degree of degradation, it would be capable of severing from one-quarter to one-third of the rubber chains. In view of these dimensions, and the fact that natural rubber normally contains difficultly removable hetero components, and is ready to take up additional amounts of oxygen, little progress can be made in the fundamental investigation of the complex molecules without a suitably accurate technique of chemical analysis, and this applies particularly to the determination of total oxygen and total nitrogen, and also to the determination of the six types of combined oxygen likely to be present in rubber, viz., hydroxylic, oxido-, ethereal, peroxidic, carbonyl and carboxylic. Unfortunately, great precision in estimation cannot be achieved without increasing greatly the rigour of the analytical technique, and perhaps it is not surprising that Midgley, Henne and Renoll's well-known high-precision method for determining carbon, hydrogen and, by difference, oxygen, still remains after five years the sole such chemical analytical method reported in the literature.

Sign in / Sign up

Export Citation Format

Share Document