3- Mechanisms of Drug Actions §3.1 Structure-Activity Relationship § ( 构效关系 ) §Both the affinity of a drug and its functional activity are determined by its chemical structure. §Relatively minor modifications in the drug molecule may result in major changes in pharmacological properties.

Atropine Peripheral & Central ScopolamineCentral AnisodaminePeripheral

Norepinephrine  receptor Epinephrine ,  receptors Isoprenaline  receptor

§3.2 Non-specific mechanisms ( 非特异性机制 ) § （ 1 ） Physioc-chemical reactions § Antacids, mannitol, dextran, …… § （ 2 ） Membrane-stablizing § General anesthetics, ethanol, …… § （ 3 ） Disinfectants 3- Mechanisms of Drug Actions

§3.3 Specific mechanisms ( 特异性机制 ) (1) Receptor ( 受体 ) (1) Receptor ( 受体 ) (2) Enzyme ( 酶 ) (2) Enzyme ( 酶 ) (3) Ion channel ( 离子通道 ) (3) Ion channel ( 离子通道 ) (4) Transporter ( 转运体 ) (4) Transporter ( 转运体 ) (5) Immune system ( 免疫系统 ) (5) Immune system ( 免疫系统 ) (6) Gene therapy ( 基因治疗 ) & genetic (6) Gene therapy ( 基因治疗 ) & genetic engineering drugs ( 基因工程药物 ) engineering drugs ( 基因工程药物 ) (7) Others ( 其他 ) (7) Others ( 其他 ) 3- Mechanisms of Drug Actions

Specific mechanisms ： Actions on cell functions

Enzyme-targeting drugs Acetylcholinesterase inhibitor Cyclo-oxygenase inhibitor Angiotensin converting enzyme inhibitor Na + -K + -ATPase inhinitor H + -K + -ATPase inhinitor HMG-CoA reductase inhibitors Most of antibiotics and anti- tumor drugs

Drugs acting on ion channels

Furosemide inhibits Na + -K + -2Cl - - transporter Neurotransmitter transporter inhibitors

Targets of drug

4- Drug receptors Key events in the discovery and establishment of the concept of receptors

4- Drug receptors §4.1 Concept of receptors §Receptor: the component of a cell or organism that interacts with a drug and initiates the chain of biochemical events leading to the drug’s observed effects. 受体：蛋白质识别、结合配体 发生信号转导 § （ 受体：细胞膜或细胞质的特异性蛋白质，具有识别、结合配体，并 发生信号转导的作用 ） §Function: recognizing and binding with a specific ligand; signal transduction §Structure: a protein with ligand-bingding domain and effector (transducer) domain

4- Drug receptors §Ligand: Chemicals that can bind to receptors, including endogenous or exogenous agonists and antagonists 配体： §( 配体：能与受体特异性结合的物质，分为激动剂和拮抗剂； 根据来源分为内源性和外源性两类 )

4- Drug receptors Characteristics of receptor （ interaction between drug and receptor) a) Sensitivity ( 灵敏性 ) b) Specificity ( 特异性 ) b) Specificity ( 特异性 ) c) Saturability ( 饱和性 ) c) Saturability ( 饱和性 ) d) Reversibility ( 可逆性 ) d) Reversibility ( 可逆性 ) e) Multiple-variation ( 多样性 ) e) Multiple-variation ( 多样性 )

§4.2 Receptor classification §(1) G protein-coupled receptors (G 蛋白偶联受体, GPCR, 7TM 受体 ) §(2) Ligand-gated ion channel receptors ( 含离子通道的 受体，配体门控离子通道受体 ) §(3) Receptors as enzymes or coupled by enzymes § ( 具有酪氨酸激酶活性 [ 或偶联］受体, 1TM 受体 ) §(4) Cytosolic [or nuclear] receptors ( 细胞内受体, § 核内受体 ) 4- Drug receptors

Another classification (1) Cytosolic [or nuclear] receptors (1) Cytosolic [or nuclear] receptors (2) Receptors as enzymes (2) Receptors as enzymes (3) Receptors coupled by enzymes (3) Receptors coupled by enzymes (4) Ligand-gated ion channel receptors (4) Ligand-gated ion channel receptors (5) G protein-coupled receptors (5) G protein-coupled receptors

Examples: M cholinoceptor Adrenoceptors 5-HT receptors DA receptors Opioid receptors ect. G protein-coupled receptors (GPCR)

GPCR signal transduction cAMP-PKA IP 3 -Ca 2+ / PKC PKA

Ligand-gated ion channel receptors Examples: N cholinoceptor GABA A receptor 5-HT 3 receptor NMDA receptor

Receptors as enzymes Growth factor receptors Receptors coupled by enzymes Cytokine receptors

Cytosolic receptors Steroid receptors as transcript factors

Nuclear receptors: thyroid receptor as a transcript factor

§4.3 Interactions of drug and receptor §D ＋ R DR E §Occupation theory: Drug binds to its receptor, then produce physiological effects 4- Drug receptors

§Binding properties §Binding assay （ radioactive tests ） §K D ＝ [D][R] / [DR] §Bioassay （ biological effect tests ） §E/E max ＝ [DR] / [R T ] ＝ [D] / {K D +[D]} 4- Drug receptors

§ （ 1 ） Affinity （ 亲和力 ） § ability of drug to bind to the receptor §Ligand binding tests ： K D ； K B §In vitro effect test ： EC 50, pD 2 （ negative log molar concentration of the agonist which produces 50 ％ of the maximal effect ） 4- Drug receptors

§ （ 2 ） Intrinsic activity （ 内在活性 ） § Ability of drug to produce effects after binding to the receptor E/E max ＝ α·[DR] / [R T ] § E/E max ＝ α·[DR] / [R T ] 4- Drug receptors

Concentration-effect curve ： different affinity same intrinsic activity same intrinsic activity Affinity Intrinsicactivity

Concentration-effect curve ： same affinity different intrinsic activity different intrinsic activity Intrinsic activity Affinity

§4.4 Agonists and antagonists §Drugs that act on receptors can be classified into three types based on their affinity, intrinsic activity and produced physiological effect ： § Full agonist ( 激动药 ) § Partial agonist ( 部分激动药 ) § Antagonist ( 拮抗药 ) 4- Drug receptors

§Classification of drugs that acting on receptors § Affinity Intrinsic activity Effects §Agonist Yes Yes （ 100 ％） Yes §Antagonist Yes None （ 0 ％） None ， § blocking agonist §Partial Yes Weak （ 0 ～ 100 ％） Weak, §agonist blocking agonist 4- Drug receptors

Different patterns of receptor-acting drugs

Box 4 Recently ， there are new classes of drugs that act on the receptors ： inverse agonist ( 反向激动剂 ) or negative antagonist （ 负拮抗剂 ） 具有拮抗剂特点，本身又产生与激动剂相反的效应 。 co-agonist ( 协同激动剂 ) 与其它激动剂共同发挥效应 。

§4.5 Competitive and non-competitive antagonism §Competitive antagonists: that compete with agonist for the same binding site on the receptor. Response curve for the agonist are shift to the right without depression of maximal response. § 竞争性拮抗药与激动药并用时，能与激动药相互竞争与受体的结合， 降低激动药与受体的亲和力，而不降低内在活性（量效曲线平行右移， 最大效能不变） 4- Drug receptors

§Non-competitive antagonists: that cause (or not cause) a shift of the response curve to the right with depression of maximal response. § 非竞争性拮抗药与激动药并用时，可使亲和力及内在活性均降低，一 般可影响受体功能或与受体不可逆性结合 。 §Because of §Irreversible or pseudo-irreversible binding §Allosteric effects 4- Drug receptors

A ： Effect of a competitive antagonist on agonist concentration- response curve B ： Effect of a non-competitive antagonist on agonist concentration-response curve agonist agonist Antagonist none lowerhigher none lower higher Antagonist

Possible mechanisms of antagonisms 竞争 不可逆 / 假 不可逆 变构

Possible mechanisms of antagonisms

§Competitive antagonists: § Affinity is determined by agonist-antagonist interaction: § [A'] / [A] － 1 ＝ [I] / K I § log {[A'] / [A] － 1} ＝ log [I] － logK I § if [A' ] / [A] ＝ 2, then § log [I] ＝ log K I ＝ pA 2 4- Drug receptors

Log ( [A’ ]/[A]-1) -log molar concentration of antagonist or -log [I] 0 If [A’ ] = 2[A] Then Log ( [A’]/[A]-1) = 0 pA2pA2pA2pA2 Schild plot for calculating the affinity of an antagonist

§pA 2 is the negative logarithm of the molar antagonist concentration, in the presence of which twice the original agonist concentration is needed for the original effect. §pA 2 is equal to the negative logarithm of the given concentration of the antagonist if log([A’/A]-1) equals zero. 4- Drug receptors

§pA 2 可定义为当一定浓度竞争性拮抗药存在时， 激动药浓度需要提高一倍才能达到原来的效应， 此时的竞争性拮抗药浓度的负对数值即为 pA 2 。 §pA 2 可定义为：当一定浓度竞争性拮抗药存在时， 激动药浓度需要提高一倍才能达到原来的效应， 此时的竞争性拮抗药浓度的负对数值即为 pA 2 。 §pA 2 的含义：在实验系统中加入拮抗药后，若 2 倍 浓度的激动药所产生的效应恰好等于未加入拮抗 药时激动药引起的效应，则所加入拮抗药的摩尔 浓度的负对数称为 pA 2 。 4- Drug receptors

§4.6 Regulation of receptors §(1) Desensitization （ 脱敏 ） §Receptor phosphorylation §Internalization or Endocytosis 4- Drug receptors

Reversible 同种脱敏 异种脱敏

Receptor phosphorylation

Receptor internalization

§(2) Changes of receptor numbers § Down-regulation § Down-regulation （ 向下调节，下调 ） § Up-regulation § Up-regulation （ 向上调节，上调 ） 4- Drug receptors