上海交通大学：《药理学 Pharmacology》课程教学资源（讲义课件）Chapter 3：Receptor Theory and Pharmacodynamics（1）

Chapter 3: Receptor Theory and Pharmacodynamics (1) Prof.R.D.Ye 2012-09-17

Chapter 3: Receptor Theory and Pharmacodynamics (1) Prof. R.D. Ye 2012-09-17

Pharmacodynamics is the study of the detailed mechanism of action by which drugs produce their pharmacological effects.This study starts at the binding of a drug to its target receptor or enzyme,continues through a signal transduction pathway by which the receptor activates second messenger molecules,and ends with the ultimate description of intracellular processes altered by the impact of the drug. There is also a quantitative aspect to pharmacodynamics in characterizing the dose-response curve,which is the relationship between drug dose and the magnitude of the pharmacological effect.Pharmacodynamics provides a scientific basis for the selection and use of drugs to counteract specific pathophysiologic changes due to disease or trauma

Pharmacodynamics is the study of the detailed mechanism of action by which drugs produce their pharmacological effects. This study starts at the binding of a drug to its target receptor or enzyme, continues through a signal transduction pathway by which the receptor activates second messenger molecules, and ends with the ultimate description of intracellular processes altered by the impact of the drug. There is also a quantitative aspect to pharmacodynamics in characterizing the dose-response curve, which is the relationship between drug dose and the magnitude of the pharmacological effect. Pharmacodynamics provides a scientific basis for the selection and use of drugs to counteract specific pathophysiologic changes due to disease or trauma

Study objectives Definition and characteristics of receptors Classification of Receptors Receptor activation and signal transduction ·Drug actions Classification of agonists and antagonists Dose-response relationship

• Definition and characteristics of receptors • Classification of Receptors • Receptor activation and signal transduction • Drug actions • Classification of agonists and antagonists • Dose-response relationship Study objectives

The Development of Receptor Theory Claude Bernard(1813-1878) A French physiologist,he contributed greatly to the development of experimental medicine.One of his studies was on the arrow poison curare.He asked the question of why the poison was effective when delivered by an arrow,but ineffective when taken by mouth.His work led to the understanding that the ability of a drug to elicit its effects depends on its access to a particular location

The Development of Receptor Theory Claude Bernard (1813 – 1878) A French physiologist, he contributed greatly to the development of experimental medicine. One of his studies was on the arrow poison curare. He asked the question of why the poison was effective when delivered by an arrow, but ineffective when taken by mouth. His work led to the understanding that the ability of a drug to elicit its effects depends on its access to a particular location

The Development of Receptor Theory G.G.Stokes,a physicist at Cambridge,observed in 1864 spectral changes occurred when oxygen was removed from blood or subsequently reintroduced to blood.This finding demonstrated molecular interactions between two substances,implicating a complex between oxygen and hemoglobin. As will be discussed later,one hemoglobin molecule can bind 4 oxygen molecules,and there is a positive cooperativity of binding of molecular oxygen to hemoglobin

The Development of Receptor Theory G.G. Stokes, a physicist at Cambridge, observed in 1864 spectral changes occurred when oxygen was removed from blood or subsequently reintroduced to blood. This finding demonstrated molecular interactions between two substances, implicating a complex between oxygen and hemoglobin. As will be discussed later, one hemoglobin molecule can bind 4 oxygen molecules, and there is a positive cooperativity of binding of molecular oxygen to hemoglobin

The Development of Receptor Theory Paul Erhlich(1854-1915)was a German bacteriologist who attempted to find a 'magic bullet'to cure syphilis and was a pioneer in the study of immunology.One of his findings was made when he incubated toxins with anti-toxins in a test tube.Erhlich found that antigen- antibody interactions are direct chemical encounters and not generalized phenomena as they require an ongoing biological process in the whole body.He also coined the term "chemotherapeutic index",meaning the ratio of the minimal curative dose to the maximal tolerated dose

The Development of Receptor Theory Paul Erhlich (1854-1915) was a German bacteriologist who attempted to find a 'magic bullet' to cure syphilis and was a pioneer in the study of immunology. One of his findings was made when he incubated toxins with anti-toxins in a test tube. Erhlich found that antigen￾antibody interactions are direct chemical encounters and not generalized phenomena as they require an ongoing biological process in the whole body. He also coined the term “chemotherapeutic index”, meaning the ratio of the minimal curative dose to the maximal tolerated dose

The Development of Receptor Theory John Newport Langley(1852-1926),a British physiologist, first coined the term "receptive substance".His work described curare as a blocker of neuromuscular transmission,as he was able to show that curare also could block chemical stimulation of frog gastrocnemius muscle by nicotine,without motor nerves.Therefore, there is a mutual antagonism between nicotine and curare,and the effect of which depends on the relative concentration of each.He also worked on atropine and pilocarpine,and the work led to the hypothesis that both atropine and pilocarpine could form a complex with a common substance at the nerve end,which we now know are the muscarinic receptors

The Development of Receptor Theory John Newport Langley (1852-1926), a British physiologist, first coined the term “receptive substance”. His work described curare as a blocker of neuromuscular transmission, as he was able to show that curare also could block chemical stimulation of frog gastrocnemius muscle by nicotine, without motor nerves. Therefore, there is a mutual antagonism between nicotine and curare, and the effect of which depends on the relative concentration of each. He also worked on atropine and pilocarpine, and the work led to the hypothesis that both atropine and pilocarpine could form a complex with a common substance at the nerve end, which we now know are the muscarinic receptors

The Development of Receptor Theory Langley's work also led to the concept that the rate of combination(binding)and the saturable effects are characteristic of drug and receptor interactions.This concept was not readily accepted at that time.For instance,Henry H.Dale(1875-1968)thought that the differential effectiveness of adrenaline analogues in mimicking sympathetic functions in varying tissues does not necessarily imply the existence of specific chemical receptors on target tissues.Eventually, experimental data prove the presence of specific receptors for these (as we know today) pharmacological interactions

The Development of Receptor Theory Langley’s work also led to the concept that the rate of combination (binding) and the saturable effects are characteristic of drug and receptor interactions. This concept was not readily accepted at that time. For instance, Henry H. Dale (1875-1968) thought that the differential effectiveness of adrenaline analogues in mimicking sympathetic functions in varying tissues does not necessarily imply the existence of specific chemical receptors on target tissues. Eventually, experimental data prove the presence of specific receptors for these (as we know today) pharmacological interactions

Receptors as Enzymes: nicotinic acetylcholine R G Protein-Coupled Receptor Systems glutamate R binding GABAA R glycine R 5HTa serotonin R G protein- coupled receptors Cell Surface Multisubunit Ligand-gated lon channels GTP GDP catalysis Catalytic Activities: G Proteins: Effectors Tyrosine kinases growth factor receptors Defined by Regulated by Cytoplasm neurotrophic factor receptors a Subunit a Subunits: Tyrosine phosphatases composition Serine/threonine kinases Cs ↑adenylyl cyclase,↑Ca2+currents TGFB-receptor % adenylyl cyclase,K+currents Guanylyl cyclase 00 Ca2+currents ANF receptor da ↑phospholipase CB guanylin receptor 13 Na+/H+exchange 0 1 cGMP-phosphodiesterase(vision) Cytosolic Colit t adenylyl cyclase(olfaction) Nucleus Receptor regulated by Regulation of transcription By subunits: steroids retinoids receptor-operated K+currents thyroid hormone adenylyl cyclase phospholipase CB Figure 2-1.Structural motifs of physiological receptors and their relationships to signaling pathways

Basic qualifications for a receptor For a molecule to qualify as a receptor,it must meet at least 3 criteria: 1.In a given sample,there is finite number of receptors (saturation of binding and effect) 2.Ligand binding is specific and can be competed off by a ligand of the same or similar structure (e.g., agonists and antagonists) 3.Binding kinetics is consistent with biological effect (concentration-and time-dependency)

Basic qualifications for a receptor For a molecule to qualify as a receptor, it must meet at least 3 criteria: 1. In a given sample, there is finite number of receptors (saturation of binding and effect) 2. Ligand binding is specific and can be competed off by a ligand of the same or similar structure (e.g., agonists and antagonists) 3. Binding kinetics is consistent with biological effect (concentration- and time-dependency)