Receptor Theory and Phamacodynamics 2011.9.13. Definition and characteristics of receptors Classification of Receptors Receptor activation and signal transduction ·Drug actions Classification of agonists and antagonists Dose-response relationship 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
Receptor Theory and Phamacodynamics 2011.9.13. • Definition and characteristics of receptors • Classification of Receptors • Receptor activation and signal transduction • Drug actions • Classification of agonists and antagonists • Dose-response relationship 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 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 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 antigenantibody 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 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 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
Receptors cinProtein-Coupled Receptor Systems 5HTa serotonin R G protein- Cell Surface Multisubunit Ligand-gated lon channels GTP GDP Catalytic Activities: G Proteins: Effectors atawth factor tecentors Defined by Regulated by Cytoplasm a Subunits: composition TGFB-rec 1 adenyly cycase.t Ca2.currents guanylin recepto Nat exchange Cvtosoli Nucleus regulated by 所subunits: phospholipase CB Figure 2-1.Structural motifs of physiologice 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)
Other qualifications for a receptor High affinity:Most endogenous ligands bind to their cognate receptors with high affinities(usually in the range of nmol/L) Reversibility:In most cases,the bound ligand can be dissociated from the receptor,or replaced by another ligand that also bind to the same receptor Subtypes and subunits:Many receptors have subtypes, which are structurally and functionally similar receptors (but functions could be different).Some receptors are composed of multiple subunits Classification of receptors(by location) Cell surface receptors:Most receptors are present on cell surface,which is the boundary between intracellular environment and extracellular environment Cytoplasmic receptors:Usually participate in the transport of ligands and/or their signaling Nuclear receptors:Usually involved in transcriptional regulation
Other qualifications for a receptor • High affinity: Most endogenous ligands bind to their cognate receptors with high affinities (usually in the range of nmol/L) • Reversibility: In most cases, the bound ligand can be dissociated from the receptor, or replaced by another ligand that also bind to the same receptor • Subtypes and subunits: Many receptors have subtypes, which are structurally and functionally similar receptors (but functions could be different). Some receptors are composed of multiple subunits • Cell surface receptors: Most receptors are present on cell surface, which is the boundary between intracellular environment and extracellular environment • Cytoplasmic receptors: Usually participate in the transport of ligands and/or their signaling • Nuclear receptors: Usually involved in transcriptional regulation Classification of receptors (by location)