Synthesis and structure-activity relationships of a new model of arylpiperazines .2. Three-dimensional quantitative structure-activity relationships of hydantoin-phenylpiperazine derivatives with affinity for 5-HT1A and alpha(1) receptors. A comparison of CoMFA models

被引:67
作者
LopezRodriguez, M
Rosado, ML
Benhamu, B
Morcillo, MJ
Fernandez, E
Schaper, KJ
机构
[1] UNIV NACL EDUC DISTANCIA, FAC CIENCIAS, E-28040 MADRID, SPAIN
[2] BORSTEL RES CTR, D-23845 BORSTEL, GERMANY
关键词
D O I
10.1021/jm960744g
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
A series of 48 bicyclohydantoin-phenylpiperazines (1-4) with affinity for 5-HT1A and alpha(1) receptors was subjected to three-dimensional quantitative structure-affinity relationship analysis using comparative molecular field analysis (CoMFA), in order to get insight into the structural requirements that are responsible for 5-HT1A/alpha(1) selectivity. Good models (high cross-validation correlations and predictive power) were obtained for 5-HT1A and alpha(1) receptors. The resulting 3D-QSAR models rationalize steric and electrostatic factors which modulate binding to 5-HT1A and alpha(1) receptors. A comparison of these models gives an additional understanding for 5-HT1A/alpha(1) selectivity: (a) Substitution at the ortho position by a group with negative potential is favorable to affinity for both receptors. (b) The meta position seems to be implicated in 5-HT1A/alpha(1) selectivity. While the 5-HT1A receptor is able to accommodate bulky substituents in the region of its active site, the steric requirements of the alpha(1) receptor are more restricted (optimum volume of substituent 11-25 Angstrom(3)). (c) For both receptors the para position represents a region where the volume accessible by the ligands is limited. (d) The hydantoin moiety and the side chain length seem to modulate not only the affinity but also 5-HT1A/alpha(1) selectivity. The 3D-QSAR models reveal an useful predictive information for the design of new selective ligands.
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页码:1648 / 1656
页数:9
相关论文
共 22 条
  • [1] [H-3]PRAZOSIN BINDING TO CENTRAL NERVOUS-SYSTEM REGIONS OF MALE AND FEMALE RATS
    AMBROSIO, E
    MONTERO, MT
    FERNANDEZ, I
    AZUARA, MC
    ORENSANZ, LM
    [J]. NEUROSCIENCE LETTERS, 1984, 49 (1-2) : 193 - 197
  • [2] [Anonymous], 3D QSAR DRUG DESIGN
  • [3] 2,4-DIAMINO-6,7-DIMETHOXYQUINAZOLINES .1. 2-[4-(1,4-BENZODIOXAN-2-YLCARBONYL)PIPERAZIN-1-YL] DERIVATIVES AS ALPHA-1-ADRENOCEPTOR ANTAGONISTS AND ANTIHYPERTENSIVE AGENTS
    CAMPBELL, SF
    DAVEY, MJ
    HARDSTONE, JD
    LEWIS, BN
    PALMER, MJ
    [J]. JOURNAL OF MEDICINAL CHEMISTRY, 1987, 30 (01) : 49 - 57
  • [4] CHENG Y, 1973, BIOCHEM PHARMACOL, V22, P3099
  • [5] 1,9-ALKANO-BRIDGED 2,3,4,5-TETRAHYDRO-1H-3-BENZAZEPINES WITH AFFINITY FOR THE ALPHA-2-ADRENOCEPTOR AND THE 5-HT1A RECEPTOR
    CLARK, RD
    WEINHARDT, KK
    BERGER, J
    FISHER, LE
    BROWN, CM
    MACKINNON, AC
    KILPATRICK, AT
    SPEDDING, M
    [J]. JOURNAL OF MEDICINAL CHEMISTRY, 1990, 33 (02) : 633 - 641
  • [6] COMPARATIVE MOLECULAR-FIELD ANALYSIS (COMFA) .1. EFFECT OF SHAPE ON BINDING OF STEROIDS TO CARRIER PROTEINS
    CRAMER, RD
    PATTERSON, DE
    BUNCE, JD
    [J]. JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1988, 110 (18) : 5959 - 5967
  • [7] Dakin HD, 1920, J BIOL CHEM, V44, P499
  • [8] THE DEVELOPMENT AND USE OF QUANTUM-MECHANICAL MOLECULAR-MODELS .76. AM1 - A NEW GENERAL-PURPOSE QUANTUM-MECHANICAL MOLECULAR-MODEL
    DEWAR, MJS
    ZOEBISCH, EG
    HEALY, EF
    STEWART, JJP
    [J]. JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1985, 107 (13) : 3902 - 3909
  • [9] Dunn W.J., 1984, Quant Struct. Act. Relat, P131, DOI 10.1002/qsar.19840030402
  • [10] El-Bermawy M.A., 1992, MED CHEM RES, V2, P290