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1、分子药理学,1,教学大纲,中文名称 分子药理学英文名称 Molecular Pharmacology课内总学时：32教学方式：讲授撰写人：晏为力考核方式：考试+论文报告开课学期： 学分数: 2内容偏重：理论教学要求及目的使学生了解分子药理学的基础知识和各系统分子药理学的进展，为从事药学基础研究工作和新药开发奠定理论基础。,2,课程内容,内容 授课人 日期1绪论: 分子药理学研究内容, 药物作用的机制 晏为力 9/112受体药理及信号传导 9/183细胞内第二信使蛋白激酶及有关药物进展 9/254炎症介质与抗炎药物 10/95抗糖尿病药物 谭睿 10/166缺血再灌注性损伤的分子机制 10/23
2、7抗体及生物技术药物分子药理学基础 喻凯 10/308离子通道和抗心律失常药理 11/69高血压药的分子药理学 11/1310细胞色素p450及调控 11/2011神经药理的分子药理学基础 黄新河 11/2712学习、记忆药理及老年痴呆的药物干预 12/413细胞凋亡机理及抗癌药物研究进展 12/1114氧自由基与抗氧化剂及一氧化氮 12/18考核方式： 上课情况15%， 学期论文25%，考试60%,3,分子药理学（Molecular Pharmacology),分子药理学属于一门新兴学科，其与传统药理学的最大区别就在于，它是从分子水平和基因表达的角度去阐释药物作用及其机制。The use o
3、f techniques of molecular biology to enhance the understanding of the mechanism of action of existing drugs, and with the help of molecular graphics to predict the structure of novel drugs, especially compounds that might bind to proteins of known structure.近代药理学的进展，主要表现在受体理论、离子通道、信息传递、细胞因子等分子水平上的研究
4、突破。分子药理学是指其学科层次、水平上的科学性和先进性达到“分子水平 ”，且又属于“药理学”范畴，分子生物学等相关学科的基础知识贯穿其中。,4,药物的作用机制,ReceptorsDrug/receptors and biological responsesSecond-messenger systemsThe chemistry of drug-receptor bindingDynamics of drug-receptor bindingDose response relationshipPotency and intrinsic activityDrug antagonism,5,Rec
5、eptor,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 structure is called a receptor.Receptor + Drug ? Complex ? ? ? Responses,6,DRUG RECEPTORS AND BIOLOGICALRESPONSES,Recepto
6、r: molecular substances or macromolecules in tissues that combine chemically with the drug.Ach receptor Na influx action potential increased free Ca contractionSpecific receptive substances serve as triggers of cellular reactions.,7,Agonist vs Antagonist,Chemicals that interact with a receptor to in
7、itiate a cellular reaction are termed agonists.Antagonist interacts with the receptor and prevents the interaction of agonist with its receptor.,8,SECOND-MESSENGER SYSTEMS,Many receptors are capable of initiating a chain of events involving second messengers.G proteins, short for guanine nucleotideb
8、inding proteins. G proteins have the capacity to bind guanosine triphosphate (GTP) and hydrolyze it to guanosine diphosphate (GDP).Receptor activation, G protein, adenylyl cyclase, ATP-cAMP, kinases activation, protein phosphorylation. Which G protein couples with the receptor Which kinase is activa
9、ted Which proteins are accessible for the kinase to phosphorylate,9,The specific binding sites for agonists occur at the extracellular surface, while the interaction with G proteins occurs with the intracellular portionsof the receptor. The general term for any chain of events initiated by receptor
10、activation is signal transduction.,10,11,THE CHEMISTRY OF DRUGRECEPTORBINDING,covalent bond: irreversible Covalent bond formation is a desirable feature of an antineoplastic or antibiotic drugionic bond results from the electrostatic attraction that occurs between oppositely charged ions.hydrogen bo
11、nd & Van der Waals bondsstructureactivity relationships,12,DYNAMICS OF DRUGRECEPTORBINDING,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 der Waals bond or
12、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 association and dissociation,13,DOSERESPONSE RELATIONSHIP,The relationship between the drug and the
13、 biological effect it produces.,14,Quantal Relationships,Dose (plotted on the horizontal axis) is evaluated against the percentage of animals in the experimental population that is protected by each dose (vertical axis).,The sigmoid shape is a characteristic of most doseresponse curves when the dose
14、 is plotted on a geometric, or log scale.,15,Therapeutic 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 therapeutic index.,LD1/ED99: comparison of the low
15、est dose that produces toxicity (e.g., LD1) and the highest dose that produces a maximal therapeutic response (e.g., ED99).,16,Protective Index,Usually, undesirable side effects occur in doses lower than the lethal doses. For example, phenobarbital induces drowsiness and an associated temporary neur
16、ological impairment. Since anticonvulsant drugs are intended to allow people with epilepsy to live normal 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
17、 is called a protective index.,17,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 drug a or drug b. Drug c is saidto have a lower intrinsic
18、 activity than the other two.,18,DRUG ANTAGONISM,Chemical Antagonism: Chemical antagonism involves a direct chemical interaction between the agonist and antagonist.Functional Antagonism: Functional antagonism is a term used to represent the interaction of two agonists that act independently of each
19、other but happen to cause opposite effects.Competitive Antagonism: Competitive antagonism 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 response; that is, the antagonist has little or no efficacy.,19,Equilibrium vs non- equilibiurm,20,Noncompetitive Antagonism,21,
