分子藥理學(xué)1

1、分子藥理學(xué),晏為力,教學(xué)大綱,中文名稱(chēng) 分子藥理學(xué)英文名稱(chēng) Molecular Pharmacology 課內(nèi)總學(xué)時(shí)：32教學(xué)方式：講授撰寫(xiě)人：晏為力考核方式：考試+論文報(bào)告開(kāi)課學(xué)期： Ⅰ學(xué)分?jǐn)?shù): 2內(nèi)容偏重：理論   教學(xué)要求及目的   １．使學(xué)生了解分子藥理學(xué)的基礎(chǔ)知識(shí)和各系統(tǒng)分子藥理學(xué)的進(jìn)展，為從事藥學(xué)基礎(chǔ)研究工作和新藥開(kāi)發(fā)奠定

2、理論基礎(chǔ)。,課程內(nèi)容,內(nèi)容 授課人 日期1．緒論: 分子藥理學(xué)研究?jī)?nèi)容, 藥物作用的機(jī)制 晏為力 9/112．受體藥理及信號(hào)傳導(dǎo)

3、 9/183．細(xì)胞內(nèi)第二信使蛋白激酶及有關(guān)藥物進(jìn)展 9/254．炎癥介質(zhì)與抗炎藥物

4、 10/9 5．抗糖尿病藥物 譚睿 10/166．缺血再灌注性損傷的分子機(jī)制

5、 10/23 7．抗體及生物技術(shù)藥物分子藥理學(xué)基礎(chǔ) 喻凱 10/308．離子通道和抗心律失常藥理

6、 11/69．高血壓藥的分子藥理學(xué) 11/1310．細(xì)胞色素p450及調(diào)控

7、 11/20 11．神經(jīng)藥理的分子藥理學(xué)基礎(chǔ) 黃新河 11/2712．學(xué)習(xí)、記憶藥理及老年癡呆的藥物干預(yù) 12/413．細(xì)胞凋

8、亡機(jī)理及抗癌藥物研究進(jìn)展 12/1114．氧自由基與抗氧化劑及一氧化氮 12/18 考核方式： 上課情況15%， 學(xué)期論文25%，考試60%,分子藥理學(xué)

9、（Molecular Pharmacology),分子藥理學(xué)屬于一門(mén)新興學(xué)科，其與傳統(tǒng)藥理學(xué)的最大區(qū)別就在于，它是從分子水平和基因表達(dá)的角度去闡釋藥物作用及其機(jī)制。The use of techniques of molecular biology to enhance the understanding of the mechanism of action of existing drugs, and with the help o

10、f molecular graphics to predict the structure of novel drugs, especially compounds that might bind to proteins of known structure.近代藥理學(xué)的進(jìn)展，主要表現(xiàn)在受體理論、離子通道、信息傳遞、細(xì)胞因子等分子水平上的研究突破。分子藥理學(xué)是指其學(xué)科層次、水平上的科學(xué)性和先進(jìn)性達(dá)到“分子水平 ”，且又屬于“藥理學(xué)”范

11、疇，分子生物學(xué)等相關(guān)學(xué)科的基礎(chǔ)知識(shí)貫穿其中。,藥物的作用機(jī)制,ReceptorsDrug/receptors and biological responsesSecond-messenger systemsThe chemistry of drug-receptor bindingDynamics of drug-receptor bindingDose response relationshipPotency and i

12、ntrinsic activityDrug antagonism,Receptor,A fundamental concept of pharmacology: to initiate an effect in a cell, most drugs combine with some molecular structure on the surface of or within the cell.This molecular str

13、ucture is called a receptor.Receptor + Drug ? Complex ? ? ? Responses,DRUG RECEPTORS AND BIOLOGICALRESPONSES,Receptor: molecular substances or macromolecules in tissues that combine chemical

14、ly with the drug.Ach receptor → Na influx → action potential → increased free Ca → contractionSpecific receptive substances serve as triggers of cellular reactions.,Agonist vs Antagonist,Chemicals that interact

15、with a receptor to initiate a cellular reaction are termed agonists.Antagonist interacts with the receptor and prevents the interaction of agonist with its receptor.,SECOND-MESSENGER SYSTEMS,Many receptors are capable o

16、f initiating a chain of events involving second messengers.G proteins, short for guanine nucleotide–binding proteins. G proteins have the capacity to bind guanosine triphosphate (GTP) and hydrolyze it to guanosine dipho

17、sphate (GDP).Receptor activation, G protein, adenylyl cyclase, ATP-cAMP, kinases activation, protein phosphorylation. ? Which G protein couples with the receptor ? Which kinase is activated ? Which pr

18、oteins are accessible for the kinase to phosphorylate,The specific binding sites for agonists occur at the extracellular surface, while the interaction with G proteins occurs with the intracellular portionsof the recept

19、or. The general term for any chain of events initiated by receptor activation is signal transduction.,THE CHEMISTRY OF DRUG–RECEPTORBINDING,covalent bond: irreversible Covalent bond formation is a desirable feature

20、of an antineoplastic or antibiotic drugionic bond results from the electrostatic attraction that occurs between oppositely charged ions.hydrogen bond & Van der Waals bondsstructure–activity relationships,DYNAMICS

21、 OF DRUG–RECEPTORBINDING,the electrostatic attraction of the ionic is the first force that draws the ionized molecule toward the oppositely charged receptor surface.ionic bond must be reinforced by a hydrogen or van de

22、r Waals bond or both before significant receptor activation can occur.The better the structural fit between drug and its receptor, the more secondary (i.e., hydrogen and van der Waals) bonds can form.Continual random a

23、ssociation and dissociation,DOSE–RESPONSE RELATIONSHIP,The relationship between the [drug] and the biological effect it produces.,Quantal Relationships,Dose (plotted on the horizontal axis) is evaluated against the perce

24、ntage of animals in the experimental population that is protected by each dose (vertical axis).,The sigmoid shape is a characteristic of most dose–response curves when the dose is plotted on a geometric, or log scale.,Th

25、erapeutic Index,Effective Dose ED50 (effective dose, 50%; i.e., the dose that would protect 50% of the animals).Lethal Dose percent of animals killed by phenobarbital against dose,LD50/ED50; this is the therapeu

26、tic index.,LD1/ED99: comparison of the lowest dose that produces toxicity (e.g., LD1) and the highest dose that produces a maximal therapeutic response (e.g., ED99).,Protective Index,Usually, undesirable side effects occ

27、ur in doses lower than the lethal doses. For example, phenobarbital induces drowsiness and an associated temporary neurological impairment. Since anticonvulsant drugs are intended to allow people with epilepsy to live no

28、rmal seizure-free lives, sedation is not acceptable. Thus, an important measure of safety for an anticonvulsant would be the ratio ED50 (neurological impairment)/ED50 (seizure protection). This ratio is called a protecti

29、ve index.,Potency and Intrinsic Activity,Drugs a and b produce the same maximum response.,Drug a is more potent, that is, less of drug a is needed to produce a given response.,Drug c has less maximum effect than either d

30、rug a or drug b. Drug c is saidto have a lower intrinsic activity than the other two.,DRUG ANTAGONISM,Chemical Antagonism: Chemical antagonism involves a direct chemical interaction between the agonist and antagonis

31、t.Functional Antagonism: Functional antagonism is a term used to represent the interaction of two agonists that act independently of each other but happen to cause opposite effects.Competitive Antagonism: Competitive a

32、ntagonism is the most frequently encountered type of drug antagonism in clinical practice. The antagonist combines with the same site on the receptor as does the agonist, but unlike the agonist, does not induce a respons