Relevance of theoretical molecular descriptors in quantitative structure-activity relationship analysis of alpha1-adrenergic receptor antagonists.

A quantitative structure-activity relationship (QSAR) study of a wide series of structurally diverse alpha1-adrenergic receptor antagonists was performed using the CODESSA (Comprehensive Descriptors for Structural and Statistical Analysis) technique. Theoretical descriptors derived on a single structure and ad hoc defined size and shape descriptors were considered in the attempt of describing information relevant to receptor interaction. The relative effectiveness of these two classes of parameters in developing QSAR models for native (alpha1A and alpha1B) and cloned (alpha1a, alpha1b, and alpha1d) adrenergic receptor binding affinity, functional activity of vascular and lower urinary tract tissues, and in vitro and in vivo selectivity was evaluated.

[1]  L B Kier,et al.  Use of molecular negentropy to encode structure governing biological activity. , 1980, Journal of pharmaceutical sciences.

[2]  Paul R. Yarnold,et al.  Reading and Understanding Multivariate Statistics , 1995 .

[3]  M. Cocchi,et al.  Conformational analysis, molecular modeling and quantitative structure-activity relationship studies of 2,4-diamino-6,7-dimethoxy-2-substituted quinazoline α1-adrenergic antagonists , 1991 .

[4]  M. Cocchi,et al.  Theoretical quantitative size and shape activity and selectivity analyses of 5-HT1A serotonin and α1-adrenergic receptor ligands , 1994 .

[5]  M. Karelson,et al.  Theoretical descriptors in quantitative structure-affinity and selectivity relationship study of potent N4-substituted arylpiperazine 5-HT1A receptor antagonists. , 1998, Bioorganic & medicinal chemistry.

[6]  M. Karelson,et al.  Quantum-Chemical Descriptors in QSAR/QSPR Studies. , 1996, Chemical reviews.

[7]  K. Minneman,et al.  Subtypes of α1adrenoceptors in rat blood vessels , 1990 .

[8]  Peter C. Jurs,et al.  Descriptions of molecular shape applied in studies of structure/activity and structure/property relationships , 1987 .

[9]  M. Karelson,et al.  Correlation of Boiling Points with Molecular Structure. 1. A Training Set of 298 Diverse Organics and a Test Set of 9 Simple Inorganics , 1996 .

[10]  J. Hieble,et al.  Alpha- and beta-adrenoceptors: from the gene to the clinic. 1. Molecular biology and adrenoceptor subclassification. , 1995, Journal of medicinal chemistry.

[11]  J. Blagg,et al.  Pharmacological options in the treatment of benign prostatic hyperplasia. , 1997, Journal of medicinal chemistry.

[12]  Eamonn F. Healy,et al.  Development and use of quantum mechanical molecular models. 76. AM1: a new general purpose quantum mechanical molecular model , 1985 .

[13]  M. Cocchi,et al.  Molecular modelling and quantitative structure-activity relationship analysis using theoretical descriptors of 1,4-benzodioxan (WB-4101) related compounds α1-adrenergic antagonists , 1992 .

[14]  M. Cocchi,et al.  Computer modeling of size and shape descriptors of alpha 1-adrenergic receptor antagonists and quantitative structure-affinity/selectivity relationships. , 1998, Methods.

[15]  M. Cocchi,et al.  Conformational analysis and theoretical quantitative size and shape-affinity relationships of N4-protonated N1-arylpiperazine 5-HT1A serotoninergic ligands , 1997 .

[16]  Marina Cocchi,et al.  Use of the Supermolecule Approach to Derive Molecular Similarity Descriptors for QSAR Analysis , 1998 .

[17]  Gerhard Klebe,et al.  What Can We Learn from Molecular Recognition in Protein–Ligand Complexes for the Design of New Drugs? , 1996 .

[18]  T. Langer,et al.  Novel potent and selective central 5-HT3 receptor ligands provided with different intrinsic efficacy. 1. Mapping the central 5-HT3 receptor binding site by arylpiperazine derivatives. , 1998, Journal of medicinal chemistry.

[19]  M. Karelson,et al.  QSPR: the correlation and quantitative prediction of chemical and physical properties from structure , 1995 .

[20]  P. Jurs,et al.  Development and use of charged partial surface area structural descriptors in computer-assisted quantitative structure-property relationship studies , 1990 .