E-FLUPENTIXOL


Synonyms	.beta.-flupenthixol E-flupenthixol E-flupentixol Flupenthixol Flupentixol, (e)- Flupentixole Trans-flupenthixol Trans-flupentixol
Status
Molecule Category	UNKNOWN
UNII	895OJP78MJ
EPA CompTox	DTXSID50110027


Active Pharmaceutical Ingredients Bioactive chemicals	Exact Similarity SubStructure	Threshold (%) >= 70

Structure


InChI Key	NJMYODHXAKYRHW-BLLMUTORSA-N
Smiles	OCCN1CCN(CC/C=C2\c3ccccc3Sc3ccc(C(F)(F)F)cc32)CC1
InChI	InChI=1S/C23H25F3N2OS/c24-23(25,26)17-7-8-22-20(16-17)18(19-4-1-2-6-21(19)30-22)5-3-9-27-10-12-28(13-11-27)14-15-29/h1-2,4-8,16,29H,3,9-15H2/b18-5+

Physicochemical Descriptors

Property Name	Value
Molecular Formula	C23H25F3N2OS
Molecular Weight	434.53
AlogP	4.6
Hydrogen Bond Acceptor	4.0
Hydrogen Bond Donor	1.0
Number of Rotational Bond	5.0
Polar Surface Area	26.71
Molecular species	NEUTRAL
Aromatic Rings	2.0
Heavy Atoms	30.0

Reference

Journal : J. Med. Chem.

Title : New antipsychotic agents with serotonin and dopamine antagonist properties based on a pyrrolo[2,1-b][1,3]benzothiazepine structure.

PubMed ID : 9748351

DOI : 10.1021/jm9706832

Year : 1998

Volume : 41

Issue : 20

First Page : 3763

Last Page : 3772

Authors : Campiani G, Nacci V, Bechelli S, Ciani SM, Garofalo A, Fiorini I, Wikström H, de Boer P, Liao Y, Tepper PG, Cagnotto A, Mennini T.

Abstract : The development of a synthetic approach to the novel pyrrolo[2, 1-b][1,3]benzothiazepine and its derivatives and their biological evaluation as potential antipsychotic drugs are described. In binding studies these compounds proved to be potent 5-HT2, D2, and D3 receptor ligands. The more potent benzothiazepine (+/-)-3b was resolved into its enantiomers by using HPLC techniques. In vitro testing confirmed that (-)-3b is a more potent D2 receptor ligand, maintaining high affinity for 5-HT2 receptors. In contrast, the (+)-3b enantiomer presents a 35 times higher affinity for 5-HT2 than for dopamine D2 receptors with a similar dopamine D1 receptor affinity to that of (-)-3b. Overall, (+)-3b shows an "atypical" neuroleptic binding profile, while (-)-3b has a more "classical" profile. Furthermore pharmacological and biochemical testing displayed that the novel benzothiazepine (+/-)-3b is able to increase the extracellular levels of dopamine in the rat striatum and causes a dose-related suppression of apomorphine-induced locomotor activity. At low doses (+/-)-3b does not induce catalepsy, showing atypical antipsychotic properties similar to those of olanzapine. These heterocyclic compouds represent new leads for the development of novel antipsychotic drugs with atypical properties.

Reference

Journal : J. Med. Chem.

Title : New benzocycloalkylpiperazines, potent and selective 5-HT1A receptor ligands.

PubMed ID : 9083484

DOI : 10.1021/jm950759z

Year : 1997

Volume : 40

Issue : 6

First Page : 952

Last Page : 960

Authors : el Ahmad Y, Laurent E, Maillet P, Talab A, Teste JF, Dokhan R, Tran G, Ollivier R.

Abstract : A series of 1-(benzocycloalkyl)-4-(benzamidolkyl)piperazine derivatives was prepared in order to obtain compounds with a high affinity and selectivity for 5-HT1A receptors. The modifications of aromatic substituents, the length of the alkyl chain, and the size of the ring were explored. Most of N-(1,2,3,4-tetrahydronaphthyl)-N'-(benzamidoethyl)piperazines (32-37) were bound to 5-HT1A receptors in a nanomolar range and presented a high degree of selectivity. After resolution, levorotatory enantiomers showed affinity and selectivity higher than those of dextrorotory ones for 5-HT1A sites. The agonist type activity of selected derivatives was also confirmed in vitro on the inhibition of the activation of adenylate cyclase induced by forskolin and, in vivo, on the induction of the lower lip retraction in rats.

Reference

Journal : J. Med. Chem.

Title : Conformational analysis, pharmacophore identification, and comparative molecular field analysis of ligands for the neuromodulatory sigma 3 receptor.

PubMed ID : 7990111

DOI : 10.1021/jm00050a008

Year : 1994

Volume : 37

Issue : 24

First Page : 4109

Last Page : 4117

Authors : Myers AM, Charifson PS, Owens CE, Kula NS, McPhail AT, Baldessarini RJ, Booth RG, Wyrick SD.

Abstract : Molecular modeling studies were carried out on a series of 1-phenyl-3-amino-1,2,3,4-tetrahydronaphthalenes (phenylaminotetralins, PATs), several PAT structural analogs, and various non-PAT ligands that demonstrate a range of affinities for a novel sigma 3 receptor linked to stimulation of tyrosine hydroxylase and dopamine synthesis in rodent brain. In an effort to develop a ligand-binding model for the sigma 3 receptor, a pharmacophore mapping program (DISCO) was used to identify structural features that are common to ligands that exhibit moderate to high binding affinity for sigma 3 sites. DISCO then was utilized to propose a common pharmacophoric region that included one low-energy conformation of each compound in the training set. The resulting alignment was utilized in a comparative molecular field analysis (CoMFA) study in an attempt to correlate the steric and electrostatic fields of the molecules with the respective binding affinities at the sigma 3 receptor. A suitably predictive model was obtained from the CoMFA analysis which will be employed in the development of additional PAT analogs that could potentially display high affinity and selectivity for the sigma 3 receptor. The excluded volumes which resulted from comparing molecular volumes of active and inactive compounds were visualized to examine the limits of steric tolerance imposed by the sigma 3 receptor.

Reference

Journal : Eur. J. Med. Chem.

Title : Molecular properties of psychopharmacological drugs determining non-competitive inhibition of 5-HT3A receptors.

PubMed ID : 19144451

DOI : 10.1016/j.ejmech.2008.12.003

Year : 2009

Volume : 44

Issue : 6

First Page : 2667

Last Page : 2672

Authors : Kornhuber J, Terfloth L, Bleich S, Wiltfang J, Rupprecht R.

Abstract : We developed a structure-property-activity relationship (SPAR)-model for psychopharmacological drugs acting as non-competitive 5-HT(3A) receptor antagonists by using a decision-tree learner provided by the RapidMiner machine learning tool. A single molecular descriptor, namely the molecular dipole moment per molecular weight (mu/MW), predicts whether or not a substance non-competitively antagonizes 5-HT-induced Na(+) currents. A low mu/MW is compatible with drug-cumulation in apolar lipid rafts. This study confirms that size-intensive descriptors allow the development of compact SPAR models.

Reference

Journal : J. Med. Chem.

Title : Discovery of novel inhibitors of the NorA multidrug transporter of Staphylococcus aureus.

PubMed ID : 21141825

DOI : 10.1021/jm1011963

Year : 2011

Volume : 54

Issue : 1

First Page : 354

Last Page : 365

Authors : Brincat JP, Carosati E, Sabatini S, Manfroni G, Fravolini A, Raygada JL, Patel D, Kaatz GW, Cruciani G.

Abstract : Four novel inhibitors of the NorA efflux pump of Staphylococcus aureus, discovered through a virtual screening process, are reported. The four compounds belong to different chemical classes and were tested for their in vitro ability to block the efflux of a well-known NorA substrate, as well as for their ability to potentiate the effect of ciprofloxacin (CPX) on several strains of S. aureus, including a NorA overexpressing strain. Additionally, the MIC values of each of the compounds individually are reported. A structure-activity relationship study was also performed on these novel chemotypes, revealing three new compounds that are also potent NorA inhibitors. The virtual screening procedure employed FLAP, a new methodology based on GRID force field descriptors.

Assay Description	Organism	Bioactivity
Binding affinity which represents concentration giving half-maximal inhibition of [3H]SCH-23390 (Dopamine receptor D1) binding to rat tissue homogenate	None	37.8 nM
Binding affinity of compound towards Dopamine receptor D1 using [3H]SCH-23390 (0.5 nM) ligand in striatum bovine was determined	None	18.0 nM
The compound was tested for affinity towards sigma-3 receptor	None	14.79 nM
Antagonist activity at human 5HT3A receptor expressed in HEK293 cells assessed as inhibition of serotonin-induced inward Na+ current at >= 10 uM	Homo sapiens	50.0 %
Inhibition of NorA in Staphylococcus aureus 1199B assessed as reduction in ethidium bromide efflux at 50 uM by fluorimetry after 5 mins	Staphylococcus aureus	72.0 %

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Cross References

Resources	Reference
ChEMBL	CHEMBL42055
FDA SRS	895OJP78MJ
Guide to Pharmacology	968
SureChEMBL	SCHEMBL414352
ZINC	ZINC000028643021

CONTENTS

Structure
Chemical and Physical Properties
Related Entries