Design and synthesis of 2-[4-[4-(m-(ethylsulfonamido)-phenyl)piperazin-1-yl]butyl]-1,3-dioxoperhydropyrrolo[1,2-c]imidazole (EF-7412) using neural networks.: A selective derivative with mixed 5-HT1A/D2 antagonist properties

被引:13
作者
López-Rodríguez, ML
Morcillo, MJ
Fernández, E
Rosado, ML
Orensanz, L
Beneytez, ME
Manzanares, J
Fuentes, JA
Schaper, KJ
机构
[1] Univ Complutense, Fac Ciencias Quim, Dept Quim Organ 1, E-28040 Madrid, Spain
[2] Univ Nacl Educ Distancia, Fac Ciencias, E-28040 Madrid, Spain
[3] Hosp Ramon & Cajal, E-28034 Madrid, Spain
[4] Univ Complutense, Fac Farm, Dept Farmacol, E-28040 Madrid, Spain
[5] Res Ctr, D-23845 Borstel, Germany
关键词
D O I
10.1016/S0960-894X(99)00254-1
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
A test series of 32 phenylpiperazines III with affinity for 5-HT1A and alpha(1) receptors was subjected to QSAR analysis using artificial neural networks (ANNs), in order to get insight into the structural requirements that are responsible for 5-HT1A/alpha(1) selectivity. Good models and predictive power were obtained for 5-HT1A and alpha(1) receptors. A comparison of these models gives information for the design of the new ligand EF-7412 (5-HT1A:K-i (nM)= 27; alpha(1):K-i (nM) > 1000). This derivative displayed affinity for dopamine D-2 receptor (K-i=22 nM) and is selective for all other receptor examined (5-HT2A, 5-HT3, 5-HT3, 5-HT4 and Bz). EF-7412 acts an antagonist in vivo in pre- and postsynaptic 5-MT1A receptor sites and as an antagonist in dopamine D-2 receptor. (C) 1999 Elsevier Science Ltd. All rights reserved.
引用
收藏
页码:1679 / 1682
页数:4
相关论文
共 12 条
  • [1] BAUMGARTEN HG, 1997, SEROTONINERGIC NEURO
  • [2] Dakin HD, 1920, J BIOL CHEM, V44, P499
  • [3] Functional characteristics of heterologously expressed 5-HT receptors
    Gerhardt, CC
    vanHeerikhuizen, H
    [J]. EUROPEAN JOURNAL OF PHARMACOLOGY, 1997, 334 (01) : 1 - 23
  • [4] Synthesis and structure-activity relationships of a new model of arylpiperazines.: 4.: 1-[ω-(4-arylpiperazin-1-yl)alkyl]-3-(diphenylmethylene)-2,5-pyrrolidinediones and -3-(9H-fluoren-9-ylidene)-2,5-pyrrolidinediones:: Study of the steric requirements of the terminal amide fragment on 5-HT1A affinity/selectivity
    López-Rodríguez, ML
    Morcillo, MJ
    Rovat, TK
    Fernández, E
    Vicente, B
    Sanz, AM
    Hernández, M
    Orensanz, L
    [J]. JOURNAL OF MEDICINAL CHEMISTRY, 1999, 42 (01) : 36 - 49
  • [5] 1-[ω-(4-arylpiperazin-1-yl)alkyl]-3-diphenylmethylene-2,5-pyrrolidinediones as 5-HT1A receptor ligands:: Study of the steric requirements of the terminal amide fragment on 5-HT1A affinity/selectivity
    López-Rodríguez, ML
    Morcillo, MJ
    Rovat, TK
    Fernández, E
    Sanz, AM
    Orensanz, L
    [J]. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 1998, 8 (06) : 581 - 586
  • [6] 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
    LopezRodriguez, M
    Rosado, ML
    Benhamu, B
    Morcillo, MJ
    Fernandez, E
    Schaper, KJ
    [J]. JOURNAL OF MEDICINAL CHEMISTRY, 1997, 40 (11) : 1648 - 1656
  • [7] Synthesis and structure-activity relationships of a new model of arylpiperazines .1. 2-[[4-(o-methoxyphenyl)piperazin-1-yl]methyl]-1,3-dioxoperhydroimidazo[1,5-a]pyridine: A selective 5-HT1A receptor agonist
    LopezRodriguez, ML
    Rosado, ML
    Benhamu, B
    Morcillo, MJ
    Sanz, AM
    Orensanz, L
    Beneitez, ME
    Fuentes, JA
    Manzanares, J
    [J]. JOURNAL OF MEDICINAL CHEMISTRY, 1996, 39 (22) : 4439 - 4450
  • [8] 2-[4-(o-Methoxyphenyl)piperazin-1-ylmethyl]-1,3-dioxoperhydroimidazo[1,5-a]pyridine as a new selective 5-HT1A receptor ligand
    LopezRodriguez, ML
    Morcillo, MJ
    Rosado, ML
    Benhamu, B
    Sanz, AM
    [J]. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 1996, 6 (06) : 689 - 694
  • [9] ACTIVITY OF AROMATIC SUBSTITUTED PHENYLPIPERAZINES LACKING AFFINITY FOR DOPAMINE BINDING-SITES IN A PRECLINICAL TEST OF ANTIPSYCHOTIC EFFICACY
    MARTIN, GE
    ELGIN, RJ
    MATHIASEN, JR
    DAVIS, CB
    KESSLICK, JM
    BALDY, WJ
    SHANK, RP
    DISTEFANO, DL
    FEDDE, CL
    SCOTT, MK
    [J]. JOURNAL OF MEDICINAL CHEMISTRY, 1989, 32 (05) : 1052 - 1056
  • [10] Olivier B., 1997, SEROTONIN RECEPTORS