α1-AR拮抗剂DDPH类似物的比较分子力场分析①

238JIEGOUHUAXUEVol.23,No.82004.8ChineseJ.Struct.Chem.962~968α1-ARDDPHabbaa(,210038)b(,315104)(CoMFA),()1-DDPHq2r2SEE0.457,0.953,0.2081-,:1-,,DDPHα1-(adrenergicreceptor,α1-AR)(G),GAR373()α1-AR,[1~7],(DDPH),,DDPH,,,α1-AR,DDPHα1-ARα1-AR,,,(3D-QSAR)(CoMFA)[8]11.1CoMFA3D-QSAR1988Cramer[8][9,10]CoMFA1CoMFA3(PLS)1.2[2,5~7]1TriposSYBYL6.8SGIOctane23D-QSAR21DDPH22[6](R)-DDPH[11]CACHE5.02003-11-072004-03-058632002AA2Z3118.E-mail:[e-mail].963MM3multiple-passessgiMinimizeTriposGasteiger-HckelRMS0.001kJ⋅mol1⋅nm11.DDPHTable1.StructuresandIC50ValuesoftheDDPHAnaloguesOYNR3(CH2)nR2R1*****CompoundYnR1R2R3IC50/mol.L11CHCH322-CH3;6-CH3HH0.152CHCH312-CH3;6-CH3OCH3OCH3OCH3H1.23CHCH312-CH3;6-CH3OOH0.054CHCH312-CH3;6-CH3BrH2.35CHCH312-CH3;6-CH3OHOCH3H1.26CHCH312-CH3;6-CH3H1.57CHOHCH202-CH3;6-CH3-CH(CH3)2H4.68CHOHCH222-CH3;6-CH3OCH3OCH3H129CH2CH212-CH3;6-CH3HCH31610CH2CH212-H;6-HHCH32.111CHCH322-CH3;6-CH3OCH3OCH3O2SCH30.3412(DDPH)CHCH322-CH3;6-CH3OCH3OCH3H0.1513CHCH322-CH3;6-CH3OHOCH3H0.3114CHCH322-CH3;6-CH3OOH0.6715CHCH32/OCH3OCH3H0.1716CHCH322-CH3OCH3OCH3H0.8917CHCH323-CH3OCH3OCH3H0.22OH964α1-ARDDPHNo.818*CHCH324-CH3OCH3OCH3H0.5519CHCH322-NH2,4-CH3OCH3OCH3H0.5020CHCH322-OCH3OCH3H4.1921CHCH324-OCH3OCH3H1.2222CHCH324-ClOCH3OCH3H0.1523*CHCH324-BrOCH3OCH3H0.1024*CHCH322-Cl;4-ClOCH3OCH3H2.5725*CHCH322-Br;4-Br;6-BrOCH3OCH3H30.5026*CHCH324-NO2OCH3OCH3H38.4027CHCH324-NHCOCH3OCH3OCH3H89.8028CHCH324-OCH3OCH3OCH3H0.0129*CHCH324-OCH3;3-SO2NH2OCH3OCH3H0.1113CoMFACoMFA(R)-DDPHCoMFA6(1*)Fitatoms,1SP3C,(PLS)PLSrcv222.1CoMFACoMFA[12~15](all-spacesearching,ASS)(2)SybylStaticTranslateStaticRotateSPLxyz20189162CoMFAPLSxyz0Å2Å0.5Å44464CoMFAPLS2004Vol.23JIEGOUHUAXUEChineseJ.Struct.Chem.9651.Fig.1.Mapofsuperimposition2.q2Table2.q2ValuesofDifferentGridBoxesandStepsGridboxABCDEFGX/Å–8–6–8–6–10–8–7–5–8–6–8–6–8–6Y/Å–8–14–8–14–10–16–5–13–8–14–8–14–8–14Z/Å–3–15–4–16–5–17–3–15–3–15–3–15–3–15Step/Å2.02.02.02.01.01.53.0q20.4570.1380.4500.0150.1790.1490.077n44444342A(BC),(D)(AEFG)(A)CoMFA34567845678predictedPIC50acturalPIC500.40.457(192324252629)4()0.97522■Fig.2.Comparisonbetweentheexperimentalandcalculatedbiologicalactivitiestrainingset;predictedset3.CoMFATable3.ResultsoftheCoMFAnalysesoftheTrainingSetAFractionModelq2r2Std.ErrorofestimateFNum.ofcomponetsStericElectrostaticA0.4570.9530.20873.75240.5860.414966α1-ARDDPHNo.84.Table4.ExperimentalBiologicalActivites,CalculatedActivitiesandtheResidualiNo.ActualPIC50PredictedPIC50ResidualNo.ActualPIC50PredictedPIC50Residual16.826.450.37166.056.17–0.1225.925.910.01176.666.74–0.0837.307.260.0418*6.266.42–0.1645.635.590.40196.306.240.0655.925.880.04205.385.110.2765.825.970.15215.916.30–0.3975.345.320.02226.826.690.1384.924.95–0.0323*7.006.770.2394.805.08–0.2824*5.595.670.08105.685.460.2225*4.524.300.22116.476.380.0926*4.424.690.27126.826.590.23274.054.040.01136.516.440.07288.008.12–0.12146.176.110.0629*6.966.890.07156.776.78–0.012.20.586/0.414CoMFACoMFA3(a)3(b)3(a),23(b)()2021R12021212027R1(–NHCOCH3)CH328R1(4methoxy)R2R2161718R11718171816222326R1–Cl–Br–NO2–0.080–0.060–0.1159–NO2–Cl–Br232226242524624625246Br2524121314R21121314R231213141112R311R3SO2C6H4CH3SO29109R126dimethyl269108YCHOHCH2127n=0R22004Vol.23JIEGOUHUAXUEChineseJ.Struct.Chem.967Y82456n=1R232456R22O2456R22456(a)(b)3CoMFA(a)CoMFA(b)12Fig.3.CoMFAcontourmapsofstericfield(a)andelectrostaticfield(b)withcompound12beingembedded3DDPH(CoMFA)(1)Xia,L.;Ni,P.Z.;Qian,J.Q.;Tang,W.F.CNPatent,92107623,1992–07–04.(2)Xu,J.Y.;Xia,L.;Ni,P.Z.JournalofChinaPharmaceuticalUniversity1992,23,203–208.(3)Ni,P.Z.;Peng,J.H.;Xia,L.;Fu,J.H.;Chen,Y.F.JournalofChinaPharmaceuticalUniversity1996,27,395–400.(4)Sun,H.B.;Zhu,J.W.;Ni,P.Z.;Xia,L.JournalofChinaPharmaceuticalUniversity1993,24,11–17.(5)Ni,P.Z.;Sun,H.B.;Peng,J.H.;Xia,L.;Qian,J.Q.JournalofChinaPharmaceuticalUniversity1996,27,462–465.(6)Song,W.;Zhang,Y.J.;Xia,L.;Liu,G.Q.ActaPharmaceuticaSinica1998,33,102–105.(7)Xia,L.;Ni,P.Z.;Song,W.;Liu,G.Q.ActaPharmaceuticaSinica1990,25,150–153.(8)Cramer,R.D.;Patterson,D.E.;Bunce,J.D.J.Am.Chem.Soc.1988,110,5959–5967.(9)Lee,K.W.;Briggs,J.M.J.Comput.AidedMol.Des.2001,15,41–55.(10)Sippl,W.J.Comput.AidedMol.Des.2000,14,559–572.(11)Song,S.Y.;Lin,X.Y.;Zhao,H.Y.ChineseJ.Struct.Chem.1997,16,102–106.(12)Wang,R.X.;Liu,G.;Lai,L.H.ACTAPHYSICO-CHIMICASINICA1998,14,1–3.(13)Hou,T.J.;Xu,X.J.ChemometricsandIntelligentLaboratorySystems2001,56,123–132.(14)Jung,M.;Kim,H.Bioorganic&MedicinalChemistryLetters2001,11,2041–2044.(15)Cho,S.J.;Tropsha,A.J.Med.Chem.1995,38,1060–1066968α1-ARDDPHNo.8ComparativeMolecularFieldAnalysis(CoMFA)ofα1-AdrenocepterAntagonistDDPHandItsAnaloguesXIBao-MinaZHAOWen-NabZOUJian-WeibNIPei-Zhouaa(DepartmentsofPhysicsChemistryandOrganicChemistry,ChinaPharmaceuticalUniversity,Nanjing210038,China)b(KeyLaboratoryforMolecularDesignandNutritionEngineering,NingboInstituteofTechnology,ZhejiangUniversity,Ningbo315104,China)AbstractForaseriesofphenoxyalkylaminesα1-adrenocepterantagonist(DDPHanditsanalogues),athree-dimensionalquantitative-structureacti