ELTOPRAZINE


Synonyms	DU-28853 Eltoprazine
Status
Molecule Category	UNKNOWN
UNII	510M006KO6
EPA CompTox	DTXSID5048425


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

Structure


InChI Key	WVLHGCRWEHCIOT-UHFFFAOYSA-N
Smiles	c1cc2c(c(N3CCNCC3)c1)OCCO2
InChI	InChI=1S/C12H16N2O2/c1-2-10(14-6-4-13-5-7-14)12-11(3-1)15-8-9-16-12/h1-3,13H,4-9H2

Physicochemical Descriptors

Property Name	Value
Molecular Formula	C12H16N2O2
Molecular Weight	220.27
AlogP	0.87
Hydrogen Bond Acceptor	4.0
Hydrogen Bond Donor	1.0
Number of Rotational Bond	1.0
Polar Surface Area	33.73
Molecular species	BASE
Aromatic Rings	1.0
Heavy Atoms	16.0

Reference

Journal : J. Med. Chem.

Title : 5-HT1A-versus D2-receptor selectivity of flesinoxan and analogous N4-substituted N1-arylpiperazines.

PubMed ID : 9022796

DOI : 10.1021/jm960496o

Year : 1997

Volume : 40

Issue : 3

First Page : 300

Last Page : 312

Authors : Kuipers W, Kruse CG, van Wijngaarden I, Standaar PJ, Tulp MT, Veldman N, Spek AL, IJzerman AP.

Abstract : We investigated the structural requirements for high 5-HT1A affinity of the agonist flesinoxan and its selectivity versus D2 receptors. For this purpose a series of arylpiperazine congeners of flesinoxan were synthesized and evaluated for their ability to displace [3H]-8-OH-DPAT and [3H]spiperone from their specific binding sites in rat frontal cortex homogenates and rat striatum, respectively. Variations were made in the N4-substituent and the arylpiperazine region. Effects of N4-substitution in the investigated compounds appeared to be quite similar for 5-HT1A- and D2-receptor affinity. Lipophilicity at a distance of four carbon atoms from the piperazine N4 atom seems to be the main contributing factor to affinity for both receptors. Our data show that the amide group in the flesinoxan N4-substituent is unlikely to interact with the 5-HT1A receptor but, instead, acts as a spacer. In contrast to the structure-affinity relationships (SARs) of the N4-substituents, selectivity for 5-HT1A versus D2 receptors was gained by the arylpiperazine substitution pattern of flesinoxan. Restriction of flexibility of the N4-(benzoylamino)ethyl substituent and its effect on 5-HT1A-receptor affinity and activity were also studied. Our data show that in the bioactive conformation, the N4-[(p-fluorobenzoyl)amino]ethyl substituent is probably directed anti-periplanar relative to the HN4 atom. These results were used to dock flesinoxan (1) and two of its congeners (27 and 33) into a model of the 5-HT1A receptor that we previously reported. Amino acid residues surrounding the N4-[(p-fluorobenzoyl)amino]ethyl substituent of flesinoxan and its congeners are also present in D2 receptors. In contrast, several residues that contact the benzodioxane moiety differ from those in D2 receptors. These observations from the 3D model agree with the 5-HT1A SAR data and probably account for the selectivity of flesinoxan versus D2 receptors.

Reference

Journal : J. Med. Chem.

Title : N4-unsubstituted N1-arylpiperazines as high-affinity 5-HT1A receptor ligands.

PubMed ID : 7783126

DOI : 10.1021/jm00011a014

Year : 1995

Volume : 38

Issue : 11

First Page : 1942

Last Page : 1954

Authors : Kuipers W, van Wijngaarden I, Kruse CG, ter Horst-van Amstel M, Tulp MT, IJzerman AP.

Abstract : In order to explore the structural requirements for high 5-HT1A affinity, a series of aryl-substituted N1-phenylpiperazines were synthesized and evaluated for their ability to displace [3H]-8-OH-DPAT from its specific binding sites in rat frontal cortex homogenates. We found 2-methoxy substitution to be favorable, while 4-methoxy substitution was detrimental for 5-HT1A affinity. Substitution with annelated rings at the 2,3-positions was highly favorable for all investigated compounds, with the exception of a pyrrole ring. All other substitutions, except fluoro, in this class of heterobicyclic phenylpiperazines decreased affinity in the order: ortho > para > meta. The loss of affinity in the ortho and para positions is probably due to steric factors: the substituents either cause steric hindrance with the receptor or prevent the compound from adopting the appropriate conformation for binding to the 5-HT1A receptor. Conformational analysis combined with structure-affinity relationships (SAR) indicates that our arylpiperazines may bind at the 5-HT1A receptor in a nearly coplanar conformation. Observed interactions of the compounds in our 5-HT1A receptor model appeared to be in agreement with SAR data. The aromatic part of the arylpiperazine moiety has pi-pi interactions with the aromatic residues Trp161 and Phe362 in helices IV and VI, respectively. The positively charged protonated basic nitrogen forms a hydrogen bond with the negatively charged Asp116 in helix III. The ammonium-aspartate complex is surrounded by aromatic residues Trp358 and Phe361 in helix VI. A lipophilic pocket is formed by Phe362, Leu366 (both helix VI), and the methyl group of Thr200 (helix V). In agreement with the model, addition of a methyl substituent to the structure of the benzodioxine analogue 12 in this region, yielding 13, is favorable for 5-HT1A receptor affinity. Unfavorable positions for substitution with bulky groups, like the 3- and 4-positions in the benzofuran compound 14, are explained by steric hindrance with the backbone atoms of helix V. Thus, we were able to rationalize the 5-HT1A SAR of existing N1-phenylpiperazines, as well as a series of newly synthesized bicyclic heteroarylpiperazines, in terms of receptor-ligand interactions. Several of these N4-unsubstituted compounds had affinities in the low-nanomolar range.

Reference

Journal : J. Med. Chem.

Title : Structure-affinity relationship studies on 5-HT1A receptor ligands. 1. Heterobicyclic phenylpiperazines with N4-alkyl substituents.

PubMed ID : 8410989

DOI : 10.1021/jm00071a006

Year : 1993

Volume : 36

Issue : 19

First Page : 2751

Last Page : 2760

Authors : van Steen BJ, van Wijngaarden I, Tulp MT, Soudijn W.

Abstract : Structure-affinity relationship (SAR) studies for 5-HT1A receptor site are presented for two series of heterobicyclic phenylpiperazines with N4-alkyl substituents: 4-alkyl derivatives of 1-(2,3-dihydro-1,4-benzodioxin-5-yl)piperazine (3) and 1-(benzo[b]furan-7-yl)piperazine (4). The linear and branched hydrocarbon chain derivatives up to n-decyl were synthesized and evaluated for their ability to displace [3H]-2-(di-n-propylamino)-8-hydroxytetralin from its specific binding sites in rat frontal cortex homogenates. All compounds displayed a nanomolar affinity for the 5-HT1A receptor. In both series the N-ethyl and N-n-propyl substituted derivatives have similar affinities, being slightly but statistically significantly less active than the N-methyl-substituted derivatives. Elongation of the hydrocarbon chain increases the affinity for the central 5-HT1A receptor site, reaching a local maximum for the N-n-hexyl-substituted phenylpiperazines 23 (Ki = 0.50 nM) and 39 (Ki = 0.54 nM). Assuming that the arylpiperazine derivatives at the 5-HT1A binding site are in the ionic state, ionization constants were determined in order to evaluate the use of the local inhibition constant, Ki+, as a more convenient parameter to study the structure-affinity relationships. However, the Ki+ could not account for the specific N4-substituent effects found.

Reference

Journal : J. Med. Chem.

Title : Structure-affinity relationship studies on 5-HT1A receptor ligands. 2. Heterobicyclic phenylpiperazines with N4-aralkyl substituents.

PubMed ID : 8064803

DOI : 10.1021/jm00043a015

Year : 1994

Volume : 37

Issue : 17

First Page : 2761

Last Page : 2773

Authors : van Steen BJ, van Wijngaarden I, Tulp MT, Soudijn W.

Abstract : Structure-affinity relationship (SAR) studies for the 5-HT1A receptor site are presented for two series of heterobicyclic phenylpiperazines with N4-aralkyl substituents: 4-aralkyl derivatives of 1-(2,3-dihydro-1,4-benzodioxin-5-yl)piperazine (3) and 1-(benzo[b]furan-7-yl)piperazine (4). Their affinities for 5-HT1A receptors range from 0.15 to 28 nM and thus emphasize the importance of N4-substitution. By combining the SAR of these N4-aralkyl series with the recently published SAR of the N4-alkyl-substituted phenylpiperazines, the nature of the interaction of the N4-substituted phenylpiperazines and the 5-HT1A receptor was further examined using comparative molecular field analysis (CoMFA). To discriminate between two postulated hypotheses, CoMFA models were built and validated utilizing cross-validation, bootstrapping, and randomizing techniques. The model based on a N4-substituent alignment in which all N4-substituents are equally oriented in space was selected for further evaluation. According to the CoMFA/PLS analysis, the steric and electrostatic field properties contribute in a 98:2 ratio to the affinity found for the 5-HT1A receptor. Increasing steric bulk was found to be positively as well as negatively related to affinity depending on the distance of the bulk's center from the N4-nitrogen. The location of these steric CoMFA contour levels are well defined in space when the defined alignment rules are followed. Because CoMFA does not take hydrogen bonding into account, this could indicate that the contribution of the amide function (its ability to interact through hydrogen bonding), as present in the N4-substituents, to affinity is of minor importance.

Reference

Journal : J. Med. Chem.

Title : Binding of arylpiperazines, (aryloxy)propanolamines, and tetrahydropyridylindoles to the 5-HT1A receptor: contribution of the molecular lipophilicity potential to three-dimensional quantitative structure-affinity relationship models.

PubMed ID : 8568799

DOI : 10.1021/jm950410b

Year : 1996

Volume : 39

Issue : 1

First Page : 126

Last Page : 134

Authors : Gaillard P, Carrupt PA, Testa B, Schambel P.

Abstract : A set of 280 5-HT1A receptor ligands were selected from available literature data according to predefined criteria and subjected to three-dimensional quantitative structure-affinity relationship analysis using comparative molecular field analysis. No model was obtained for serotonin analogues (19 compounds) and aminotetralins (60 compounds), despite a variety of alignment hypotheses being tried. In contrast, the steric, electrostatic, and lipophilicity fields alone and in combination yielded informative models for arylpiperazines (101 training compounds and 12 test compounds), (aryloxy)propanolamines (30 training compounds and four test compounds), and tetrahydropyridylindoles (54 training compounds) taken separately (models A, B, and C). Arylpiperazines and (aryloxy)propanolamines were then combined successfully to yield reasonably good models for 131 compounds (model D). In a last step, the three chemical classes (185 compounds) were combined, again successfully (model E). This stepwise procedure not only ascertains self-consistency in alignments but it also allows statistical signals (i.e., favorable or unfavorable regions around molecules) to emerge which cannot exist in a single chemical class. The models so obtained reveal a number of interaction sites between ligands and the 5-HT1A receptor, and extend the information gathered from a model based on homology modeling.

Reference

Journal : J. Med. Chem.

Title : Characterization of potent and selective antagonists at postsynaptic 5-HT1A receptors in a series of N4-substituted arylpiperazines.

PubMed ID : 7562940

DOI : 10.1021/jm00020a020

Year : 1995

Volume : 38

Issue : 20

First Page : 4044

Last Page : 4055

Authors : Peglion JL, Canton H, Bervoets K, Audinot V, Brocco M, Gobert A, Le Marouille-Girardon S, Millan MJ.

Abstract : Benzocycloalkyl and benzocycloalkenyl moities linked, directly or via an alkyl chain, to oxygen-bearing heteroarylpiperazines were synthesized, in an attempt to obtain potent and selective antagonists at postsynaptic 5-HT1A receptors. From the numerous arylpiperazines described in the literature, 1-(2,3-dihydro-1,4-benzodioxin-5-yl)piperazine (3a) was chosen as a model of an arylpiperazine in view of its selectivity for 5-HT1A receptors versus alpha 1-, alpha 2-, and beta-adrenergic receptors, as well as dopamine D1 and D2 receptors. Two other closely-related arylpiperazines, 1-(1,5-benzodioxepin-6-yl)piperazine (3b) and 1-(benzofuran-7-yl)piperazine (3c), were also examined in this study. All compounds showed high affinity at 5-HT1A sites (8.10 < or = pKis < or = 9.35), and the majority behaved as antagonists in vivo in blocking the hypothermia induced by the 5-HT1A agonist 8-OH-DPAT in the absence of a marked effect alone at equivalent doses. An in vivo evaluation of dopamine D2 receptor antagonist properties revealed that the majority of compounds was devoid of activity at this site, in marked contrast to BMY 7378 which displayed virtually no selectivity for 5-HT1A versus dopamine D2 receptors. Moreover, six compounds of the present series, 8, 10, 11, 14, 25, and 37, showed > 10-fold selectivity in vitro for 5-HT1A versus alpha 1-adrenergic receptors. Compound 14 displayed an optimal compromise between potency (pKi = 8.75), marked antagonist activity, and selectivity toward alpha 1-adrenergic (81-fold) and dopamine D2 (195-fold) receptors. These characteristics clearly distinguish 14 from previously-reported ligands such as the postsynaptic 5-HT1A antagonist BMY 7378 and the weak partial agonist NAN 190 which, in contrast to the compounds of this series, belong to the well-exemplified class of imido derivatives of (o-methoxyphenyl)piperazines. The availability of 14 (S 15535) should facilitate the further elucidation of the functional role and potential therapeutic significance of 5-HT1A receptors.

Reference

Journal : J. Med. Chem.

Title : Characterization of potent and selective antagonists at postsynaptic 5-HT1A receptors in a series of N4-substituted arylpiperazines.

PubMed ID : 7562940

DOI : 10.1021/jm00020a020

Year : 1995

Volume : 38

Issue : 20

First Page : 4044

Last Page : 4055

Authors : Peglion JL, Canton H, Bervoets K, Audinot V, Brocco M, Gobert A, Le Marouille-Girardon S, Millan MJ.

Reference

Journal : J. Med. Chem.

Title : Structure-affinity relationship studies on 5-HT1A receptor ligands. 1. Heterobicyclic phenylpiperazines with N4-alkyl substituents.

PubMed ID : 8410989

DOI : 10.1021/jm00071a006

Year : 1993

Volume : 36

Issue : 19

First Page : 2751

Last Page : 2760

Authors : van Steen BJ, van Wijngaarden I, Tulp MT, Soudijn W.

Assay Description	Organism	Bioactivity
Binding affinity was evaluated by determining in vitro displacement of [3H]8-OH-DPAT from the central 5-hydroxytryptamine 1A receptor recognition site in rat frontal cortex homogenate.	None	40.0 nM
Displacement of [3H]2-(di-N-propylamino)-8-hydroxytetralin from central 5-hydroxytryptamine 1A receptor recognition sites in rat frontal cortex homogenates.	None	40.0 nM
Displacement of radioligand [3H]2-(di-N-propylamino)-8-hydroxytetralin from 5-hydroxytryptamine 1A receptor in rat frontal cortex homogenate	None	40.0 nM
Binding affinity to displace [3H]2-(di-N-propylamino)-8-hydroxy-tetralin from 5-hydroxytryptamine 1A (5-HT1A) receptor in rat frontal cortex homogenates	None	40.0 nM
Binding affinity of a compound to rat brain 5-hydroxytryptamine 1A (serotonin) receptor assayed by radiolabeled [3H]-8-OH-DPAT ligand displacement	None	39.81 nM
Binding affinity at 5-hydroxytryptamine 1A receptor	None	9.333 nM
Binding affinity at 5-hydroxytryptamine 1B receptor	None	53.7 nM
Local inhibition constant was determined	None	36.6

Cross References

Resources	Reference
ChEMBL	CHEMBL282614
DrugBank	DB12883
FDA SRS	510M006KO6
PubChem	65853
SureChEMBL	SCHEMBL177715
ZINC	ZINC000000001347

CONTENTS

Structure
Chemical and Physical Properties