长效抗哮喘药沙美特罗和福莫特罗的研究进展-包雅琳

＊　(　　　100730)　近年发现的长效支气管扩张剂沙美特罗和福莫特罗是β2受体激动剂,其药效强,持续时间可长达12～24h,副作用少,适用于治疗中、重度或伴有夜间发作的哮喘。它们的长效作用机理与其分子结构有关。沙美特罗的长脂肪族侧链使其脂溶性增强,因而与细胞膜脂质层不易分离;长侧链又可与受体的附加结合位点牢固结合,从而延长药效。福莫特罗的甲酰氨基则使其内在活性及其与受体的亲和力增高,从而增强其药效;福莫特罗的中等强度脂溶性也可能在一定程度上延长其药物作用时间。　哮喘;沙美特罗;福莫特罗;受体激动剂;构效关系　　β-,ββ2。β2,,4～6h,,〔1〕。β2(salmeterol)(for-moterol),12～24h〔2〕,。1994,,〔1,2〕。10～20min,(FEV1)15%;3,(PEFR)32～39L·min-1;〔1〕。、。1　、。1,1　β2,,,4000〔3〕。　＊·282·ForeignMedicalSciencesSectiononPharmacy　1997Oct;24(5)DOI:10.13220/j.cnki.jipr.1997.05.006,N-N-,β2;,β2〔4〕。,〔5〕。2　β2,、、。2,,,,〔3〕。15〔3〕,100〔6〕,36〔7〕,〔8〕。,,、C4、D4D220h〔9〕。3　,,β2。β2,,62～67ku,733。2　-G-　　H,E,R·283·　199710　245β2Ⅲ113(、),Ⅴ204207〔10〕。β21.1nm〔11〕。β2(HR),(GTP)(G),Gα、β、γ,α(GDP)GTP,2,,GGDP,,βγα(GDP)。HRG,αGDP,GTP,βγα(GTP)。αβγ,α(GTP)(),。GGTP,GTPGGDP,α(GDP)βγβγα(GDP)〔12〕。(cAMP),cAMPcAMP(PKA,PKG)、Ca2+-ATP,、;cAMPNa+/K+,Na+/Ca2+,Ca2+,Ca2+,Ca2+,、,〔13〕。β2。Jack〔14〕:(1),(Krebs),;(2)β2(sotalol);(3),。,,。“”:;(lipophilic),(3),。,,,(),。,,。。3　β2,,,,,。,(hydrophilic),,,。(intermediate),,,,(4)〔5〕。　　,·284·ForeignMedicalSciencesSectiononPharmacy　1997Oct;24(5)4　。Anderson〔5〕,,,β2,。,cAMP,,β221。,()21,。4　50μg12mg,2〔1〕,100μg〔14〕。,,PEFRFEV1,。1,,(subsensitivity)〔1,15〕。Verberne〔16〕(50μg,2)(200μg,2),FEV1,,4。〔1〕。,,〔14,17〕,,Tilles〔1〕,,;〔17〕。,,β2〔1〕。,cAMP〔14〕。:(1)、,,50μg,2;(2),50μg;(3),〔1,18〕。,、、、Q-Tc、。,,〔1〕。〔14〕。,12/16787,(2/8393)3,〔1〕。5　(2)β2,cAMP,。、、、。、,·285·　199710　245。。、,,,,。,。1　TillesSA,NelsonHS.Long-actinginhaledβagonists.JAsthma,1995;32(6):397～4042　RabeKF,J¨orresR,NowakD,etal.Comparisonoftheeffectsofsalmeterolandformoterolonairwaytoneandresponsivenessover24hoursinbronchialasthma.AmRevRespirDis,1993;147(6):1436～14413　JeppssonAB,L¨ofdahlCG,WaldeckB,etal.Onthepredictivevalueofexperimentsinvitrointheevaluationoftheeffectdurationofbronchodilatordrugsforlocalad-ministration.PulmPharmacol,1989;2(2):81～854　TasakaT.Formoterol(Atock):aneworallyactiveandselectiveβ2receptorstimulant.DrugsToday,1986;22(5):505～5195　AndersonGP.Formoterol:pharmacology,mole-cularbasisofagonism,andmechanismoflongdurationofahighlypotentandselectiveβ2adrenoceptoragonistbron-chodilator.LifeSci,1993;52(26):2145～21606　LauHYA,WongPL,LaiCKW.Effectsofβ2a-drenergicagonistsonisolatedguineapiglungmastcells.AgentsActions,1994;42(374):92～947　KikkawaH,KannoK,IkezawaK.TA-2005,anovel,long-acting,andselectiveβ2adrenoceptoragonist:char-acterizationofitsinvivobronchodilatingactioninguineapigsandcatsincomparisonwithotherβ2agonists.BiolPharmBull,1994;17(8):1047～10528　BowdenJJ,SulakvelidzeI,McDonaldDM.Inhibitionofneutrophilandeosinophiladhesiontovenulesofrattra-cheabyβ2adrenergicagonistformoterol.JApplPhysiol,1994;77(1):397～4059　ButchersPR,VardeyCJ,JohnsonM.Salmeterol:apo-tentandlong-actinginhibitorofinflammatorymediatorreleasedfromhumanlung.BrJPharmacol,1991;104(3):672～67610　DixonRAF,SigalIS,RandsE,etal.Ligandbindingtotheβ-adrenergicreceptorinvolvesitsrhodopsin-likecore.Nature,1987;326(6108):73～7711　CollinsS.Recentperspectivesonthemolecularstructureandregulationoftheβ2adrenoceptor.LifeSci,1993;52(26):2083～209112　HeplerJR,GilmanAG.Gproteins.TrendsBio-chemSci,1992;17(10):383～38713　TorphyTJ.β-Adrenoceptors.cAMPandairwaysmoothmusclerelaxation:challengestothedogma.TrendsPharmacolSci,1994;15(10):370～37414　JackD.Awayoflookingatagonismandantagonism:lessonsfromsalbutamol,salmeterolandotherβ-adreno-ceptoragonists.BrJClinPharmacol,1991;31(5):501～51415　WeersinkEJ,DoumaRR,PostmaDS,etal.Fluticas-onepropionate,salmeterolxinafoateandtheircombina-tioninthetreatmentofnocturnalasthma.AmJRespirCritCareMed,1997;155(4):1241～124616　VerberneAAPH,HopWCJ,CreyghtonFBM,etal.Respiratorypathophysiologicresponses.Airwayrespon-sivenessafterasingledoseofsalmeterolandduringfourmonthsoftreatmentinchildrenwithasthma.JAllergyClinImmunol,1996;97(4):938～94617　BoydGonbehalfofaUKstudygroup.Salmeterolxi-nafoateinasthmaticpatientsunderconsi-derationformaintenanceoralcorticosteroidtherapy.EurRespirJ,1995;8(9):1494～149818　GongHJr,LinnWS,ShamooDA,etal.Effectofin-haledsalmeterolonsulfurdioxide-inducedbronchocon-strictioninasthmaticsubjects.Chest,1996;110(5):1229～1235(1997-05-07)·286·ForeignMedicalSciencesSectiononPharmacy　1997Oct;24(5)