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Czasopismo
2006 | 1 | 4 | 370-378
Tytuł artykułu

The α 1-adrenolytic and structural evaluation of new pyridoindole derivatives

Treść / Zawartość
Warianty tytułu
Języki publikacji
EN
Abstrakty
EN
α1 - adrenolytic activities of pyridoindole derivatives recently synthesized in the Institute of Experimental Pharmacology, Slovak Academy of Sciences, were measured. A characteristic set of derivatives (five active, one with a threshold activity and two inactive) was chosen and an elementary structure-activity study was performed. The structure and energy properties were estimated by quantum-chemical semiempirical AM1 and molecular mechanics methods. The ionization constants pKα of the individual derivatives were calculated by program Pallas or estimated by potenciometric titration. The α 1 blocking activities were measured by rat thoracic aorta model. The experimental model used was not α 1 - adrenoreceptor subtypes specific, however, the α 1D subtype could be considered to be a predominant type in a rat aorta. The obtained physico-chemical parameters were then compared with the blocking activities of the derivatives and following determining characters for α 1 - adrenolytic activities were determined: 1) the polarity of the substituted phenol ring represented by a map of molecular electrostatic potential and 2) the hexahydro-pyridine nitrogen pKα constant, which represents the ability of the compound to be protonated by physiologic pH.
Wydawca

Czasopismo
Rocznik
Tom
1
Numer
4
Strony
370-378
Opis fizyczny
Daty
wydano
2006-12-01
online
2006-10-06
Twórcy
  • Institute of Experimental Pharmacology, Slovak Academy of Sciences, 84104, Bratislava, Slovakia
  • Institute of Experimental Pharmacology, Slovak Academy of Sciences, 84104, Bratislava, Slovakia
autor
  • Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Comenius University, 832 32, Bratislava, Slovakia
  • Department of Analytical Chemistry, Faculty of Chemical and Food Technology, Slovak Technical University, 81237, Bratislava, Slovakia
Bibliografia
  • [1] J.B. Bremmer, R. Griffith and B. Coban: “Ligand Design for Alpha1 Adrenoceptors”, Current Medicinal Chemistry Vol. 8, (2001), pp. 607–620. [Crossref]
  • [2] R.M. De Marinis, M. Wise, J.P. Hieble and R.R. Ruffolo, Jr.: The alpha-1 Adrenergic Receptor, Humana Press, New Jersey, 1987.
  • [3] J.B. Bremner, B. Coban and R. Griffith: “Pharmacophore development for antagonists at α1adrenergic receptor subtypes”, J. Comp. Aid. Mol. Des., Vol. 10, (1996), pp. 545–557. http://dx.doi.org/10.1007/BF00134178[Crossref]
  • [4] J.B. Bremner, B. Coban, R. Griffith, K.M. Groenewoud and B.F. Yates: “Ligand Design for α 1 Adrenoceptor Subtype Selective Antagonists”, Bioorg. Med. Chem., Vol. 8, (2000), pp. 201–214. http://dx.doi.org/10.1016/S0968-0896(99)00263-1[Crossref]
  • [5] T. Klabunde and A. Evers: “GPCR Antitarget Modeling: Pharmacophore Models for Biogenic Amine Binding GPCRs to Avoid GPCR-Mediated Side Effects”, Chembiochem, Vol. 6, (2005), pp. 876–889. http://dx.doi.org/10.1002/cbic.200400369[Crossref]
  • [6] A. Evers and T. Klabunde: “Structure-based Drug Discovery Using GPCR Homology Modeling: Successful Virtual Screening for Antagonists of the Alpha1A Adrenergic Receptor”, J. Med. Chem., Vol. 48, (2005), pp. 1088–1097. http://dx.doi.org/10.1021/jm0491804[Crossref]
  • [7] S. Štolc, F. Považanec, V. Bauer, M. Májeková, A.L. Wilcox, V. Šnirc, L. Račková, R. Sotníková, M. Štefek, Z. Gáspárová-Kvaltínová, A. Gajdošíková and D. Mihálová: Slovak patent registration PP 1321, 2003.
  • [8] S. Štolc, V. Bauer, L. Beneš and M. Tichý: Czechoslovak Patent. AO-229067, 1983.
  • [9] L’. Horáková and S. Štolc: “Antioxidant and Pharmacodynamic Effects of Pyridoindole Stobadine” Gen. Pharmacol., Vol. 30, (1998), pp. 627–638. http://dx.doi.org/10.1016/S0306-3623(97)00300-5[Crossref]
  • [10] F.F. Vincenzi and T.R. Hinds: “Stobadine: bellwether of a broader view of drug actions”, Life Sci., Vol. 65, (1999), pp. 1857–1864. http://dx.doi.org/10.1016/S0024-3205(99)00438-5[Crossref]
  • [11] HyperChem 7.1, Hypercube, Inc. 2003.
  • [12] PALLAS 3.1.1.2, CompuDrug Chemistry Ltd. 1995.
  • [13] J.E. Faber, N. Yang and X. Xin: “Expression of α-Adrenoceptor Subtypes by Smooth Muscle Cells and Adventitial Fibroblasts in Rat Aorta and in Cell Culture”, J. Pharm. Exp. Ther., Vol. 298, (2001), pp. 441–452.
  • [14] J.B. Bremner, K. Castle, R. Griffith, P.A. Keller and D.D. Ridley: “Mining the Chemical Abstracts database with pharmacophore-based queries”, J. Mol. Graph. Model., Vol. 21, (2002), pp. 185–194. http://dx.doi.org/10.1016/S1093-3263(02)00141-9[Crossref]
Typ dokumentu
Bibliografia
Identyfikatory
Identyfikator YADDA
bwmeta1.element.-psjd-doi-10_2478_s11536-006-0033-8
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