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QSAR study of imidazoline antihypertensive drugs

Authorized Users Only
2008
Authors
Nikolić, Katarina
Filipić, Slavica
Agbaba, Danica
Article (Published version)
Metadata
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Abstract
The hypotensive effect of imidazoline ligands was attributed to both alpha(2)-adrenergic receptors and nonadrenergic imidazoline-1 receptors (I-1-R). Selective I-1-R ligands, devoid of the typical side effects of other centrally acting antihypertensive drugs, could be widely used in antihypertensive therapy. Thus, there is significant interest in developing new imidazoline analogs with higher selectivity and affinity for I-1-receptors. The quantitative structure-activity relationship (QSAR) study of 12 ligands was carried out using multilinear regression method on I-1-R and alpha(2)-adrenergic receptors binding affinities on human platelets. The compounds have been studied using Becke3LYP/3-21G (d, p) and Becke3LYP/6-31G(d, p) DFT methods. Among 42 descriptors that were considered in generating the QSAR model, three descriptors such as partial atomic charges of nitrogen in the heterocyclic moiety, distribution coefficient, and molar refractivity of the ligands resulted in a statistical...ly significant model with R-2 = 0.935 and cross-validation parameter q(pre)(2) = 0.803. The validation of the QSAR models was done by cross-validation and external test set prediction. The developed multiple linear regression models for the I-1-R ligands were aimed to link the structures to their reported I-1-R binding affinity log(1/K-i). The theoretical approach indicates that an increase in distribution coefficient and molar refractivity value, together with a decrease in average N-charge in the heterocyclic moiety of the ligands, causes better binding affinity for active site of the I-1 receptors. The developed QSAR model is intended to predict I-1-R binding affinity of related compounds and to de. ne possible physicochemical, electronical, and structural requirements for selective I-1-receptor ligands.

Keywords:
I-1-receptor / I-1-R ligands / centrally acting antihypertensives / structure activity relationship / pharmacophore
Source:
Bioorganic & Medicinal Chemistry, 2008, 16, 15, 7134-7140
Publisher:
  • Pergamon-Elsevier Science Ltd, Oxford
Projects:
  • Sinteza, kvantitativni odnosi između strukture/osobina i aktivnosti, fizičko-hemijska karakterizacija i analiza farmakološki aktivnih supstanci (RS-142071)

DOI: 10.1016/j.bmc.2008.06.051

ISSN: 0968-0896

PubMed: 18621536

WoS: 000258749500006

Scopus: 2-s2.0-84962448550
[ Google Scholar ]
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27
URI
http://farfar.pharmacy.bg.ac.rs/handle/123456789/1124
Collections
  • Radovi istraživača / Researchers’ publications
Institution
Pharmacy
TY  - JOUR
AU  - Nikolić, Katarina
AU  - Filipić, Slavica
AU  - Agbaba, Danica
PY  - 2008
UR  - http://farfar.pharmacy.bg.ac.rs/handle/123456789/1124
AB  - The hypotensive effect of imidazoline ligands was attributed to both alpha(2)-adrenergic receptors and nonadrenergic imidazoline-1 receptors (I-1-R). Selective I-1-R ligands, devoid of the typical side effects of other centrally acting antihypertensive drugs, could be widely used in antihypertensive therapy. Thus, there is significant interest in developing new imidazoline analogs with higher selectivity and affinity for I-1-receptors. The quantitative structure-activity relationship (QSAR) study of 12 ligands was carried out using multilinear regression method on I-1-R and alpha(2)-adrenergic receptors binding affinities on human platelets. The compounds have been studied using Becke3LYP/3-21G (d, p) and Becke3LYP/6-31G(d, p) DFT methods. Among 42 descriptors that were considered in generating the QSAR model, three descriptors such as partial atomic charges of nitrogen in the heterocyclic moiety, distribution coefficient, and molar refractivity of the ligands resulted in a statistically significant model with R-2 = 0.935 and cross-validation parameter q(pre)(2) = 0.803. The validation of the QSAR models was done by cross-validation and external test set prediction. The developed multiple linear regression models for the I-1-R ligands were aimed to link the structures to their reported I-1-R binding affinity log(1/K-i). The theoretical approach indicates that an increase in distribution coefficient and molar refractivity value, together with a decrease in average N-charge in the heterocyclic moiety of the ligands, causes better binding affinity for active site of the I-1 receptors. The developed QSAR model is intended to predict I-1-R binding affinity of related compounds and to de. ne possible physicochemical, electronical, and structural requirements for selective I-1-receptor ligands.
PB  - Pergamon-Elsevier Science Ltd, Oxford
T2  - Bioorganic & Medicinal Chemistry
T1  - QSAR study of imidazoline antihypertensive drugs
VL  - 16
IS  - 15
SP  - 7134
EP  - 7140
DO  - 10.1016/j.bmc.2008.06.051
ER  - 
@article{
author = "Nikolić, Katarina and Filipić, Slavica and Agbaba, Danica",
year = "2008",
url = "http://farfar.pharmacy.bg.ac.rs/handle/123456789/1124",
abstract = "The hypotensive effect of imidazoline ligands was attributed to both alpha(2)-adrenergic receptors and nonadrenergic imidazoline-1 receptors (I-1-R). Selective I-1-R ligands, devoid of the typical side effects of other centrally acting antihypertensive drugs, could be widely used in antihypertensive therapy. Thus, there is significant interest in developing new imidazoline analogs with higher selectivity and affinity for I-1-receptors. The quantitative structure-activity relationship (QSAR) study of 12 ligands was carried out using multilinear regression method on I-1-R and alpha(2)-adrenergic receptors binding affinities on human platelets. The compounds have been studied using Becke3LYP/3-21G (d, p) and Becke3LYP/6-31G(d, p) DFT methods. Among 42 descriptors that were considered in generating the QSAR model, three descriptors such as partial atomic charges of nitrogen in the heterocyclic moiety, distribution coefficient, and molar refractivity of the ligands resulted in a statistically significant model with R-2 = 0.935 and cross-validation parameter q(pre)(2) = 0.803. The validation of the QSAR models was done by cross-validation and external test set prediction. The developed multiple linear regression models for the I-1-R ligands were aimed to link the structures to their reported I-1-R binding affinity log(1/K-i). The theoretical approach indicates that an increase in distribution coefficient and molar refractivity value, together with a decrease in average N-charge in the heterocyclic moiety of the ligands, causes better binding affinity for active site of the I-1 receptors. The developed QSAR model is intended to predict I-1-R binding affinity of related compounds and to de. ne possible physicochemical, electronical, and structural requirements for selective I-1-receptor ligands.",
publisher = "Pergamon-Elsevier Science Ltd, Oxford",
journal = "Bioorganic & Medicinal Chemistry",
title = "QSAR study of imidazoline antihypertensive drugs",
volume = "16",
number = "15",
pages = "7134-7140",
doi = "10.1016/j.bmc.2008.06.051"
}
Nikolić K, Filipić S, Agbaba D. QSAR study of imidazoline antihypertensive drugs. Bioorganic & Medicinal Chemistry. 2008;16(15):7134-7140
Nikolić, K., Filipić, S.,& Agbaba, D. (2008). QSAR study of imidazoline antihypertensive drugs.
Bioorganic & Medicinal ChemistryPergamon-Elsevier Science Ltd, Oxford., 16(15), 7134-7140.
https://doi.org/10.1016/j.bmc.2008.06.051
Nikolić Katarina, Filipić Slavica, Agbaba Danica, "QSAR study of imidazoline antihypertensive drugs" 16, no. 15 (2008):7134-7140,
https://doi.org/10.1016/j.bmc.2008.06.051 .

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