Frederick W Seturner (1783-1841) Isolated morphine from opium in 1806 ( acid extraction followed by ammonium precipitation).

First isolation of an active ingredient azs a natural drug. Found that it caused sleep and indifference to pain. Claude Bernard (1813-1878)- stated that to understand the action of a given drug, it is essential to know which tissues are primarily involved and how a drug interacts with the biological system. - Discovered that the arrow poison Curare acts at neuromuscular junction to interrupt the stimulation of muscle by nerve impulses ( Localisation of site of action of drug) - CO2 interacting with hemoglobin ( specific mechanism of action) to cause toxicity. - Extended the experimental method to encompass physiology and medicine. Milieu interieur: internal steady state by functional buffering of stressors to preserve physio9logical constancy ( further developed by Walter Cannon at Harvard into the concept of homeostasis. Oswald Schmiedeberg (1838-1921) - Emphasised that drug activity was a consequence of a dynamic equilibrium, i.e. the drug reaching the site of action and being removed from it, with further removal from the body by hepatic metabolism and renal excretion. - In 1869, showed that muscarine evoked the same effect on the heart as electrical stimulation of the vagus nerve (i.e. a chemical could reproduce the effect of neuronal stimulation.) and that effects of both were antagonized by atropine - Introduced Urethane as a hypnotic in 1885. Otto Loewi(1873-1961)- First to identify a neurotransmitter, Ach or Vagusstoff (1921). Took fluid from one frog heart and applied it to another, slowing the second heart and showing that synaptic signaling used chemical messengers (Nobel Prize in 1936) Paul Ehrlich (1854-1915)- formulated the concept of receptors, i.e. that part of a chemical component of living tissue with which a drug combines to produce its biological effect a) Side Chain Theory: Different types of cells were characterized by different chemical chains protruding into the surrounding medium. To stain them or to interefere with their action on a host organism, on had only to find a substance with molecules on a complementary shape. Led to b) Magic Bullet namely if a compound could be made that selectively targeted a disease-causing organism ( e.g. trypanosomes), then a toxin for the organism could be delivered along with the slective agent, producing a magic bullet that killed only the orghanism targeted.

Pharmacodynamics- Study of the biochemical and physiological effects of drugs and their mechanisms of action, including the correlation of actions of drugs with their chemical structure Drug Effects- result from interaction of drugs with macromolecular components of the organism (receptor substance or receptor) so as to alter their function to initiate the biochemical and physiological changes that re characteristic of the responses. Drug cannot impart a new function on a cell, this is gene therapy Pharmacokinetics- Study of the processes affecting the fate of drugs in the body over aperiod of time, including processes such as absorption, distribution, metabolism biotransformation, and excretion. Toxicology- Study of poisons- their actions, detection and the treatment of the conditions that they produce. Pharmacogenomics How individuals genome ( full complement of genes) influences response to drugs, from either a pharmokinetic and or pharmacodynamic perspective Polymorphism- quality or character of occurring in several different forms - Restriction fragment length polymorphism - RFLP differences in DNA sequences that can result in altered expression and/or function of specific protein - Copy number variations- Deletions or duplications. Receptors for Physiological Regulatory Molecules Bind the ligand and propagate its regulatory signal in the target cell. - Direct intracellular effect (ion channel) - Indirect effect (second messenger) Functional Domains - Ligand-binding domain - Effector domain Agonists- Drugs acting on receptors for endogenous regulatory ligands (e.g. hormones, neurotransmitters) that mimic the effect of the endogenous compound; possess intrinsic activity or efficacy. This can be full or partial. Antagonist- Drugs that bind to a receptor but have no intrinsic activity; the result of such binding is interference with the effect of an agonist Inverse Agonist- A ligand that reverses constitutive receptor activity.

Endogenous Ligand Receptors 1. G-protein Coupled (many biogenic amines and peptide hormones - Facilitate binding of GTP to specific G proteins - Hydrophobic molecules that span the plasma membrane in seven alpha-helical segments - Bind GTP at their cytoplasmic face - Agonist binding site consists of a pocket formed within the bundle iof membranespanning helices. 2. Peptide Hormone Receptors- Regulate growth differentiation and development - Frequently protein kinase that act by phosphorylating target proteins on tyrosine residues - Assembled from definable domains that are distinguished in part by their location relative to the plasma membrane Nuclear Receptor Super-Family - unified by functional analogy and a characteristic punctuated sequence homology a) hormonal forms of vitamins A and D b) Steroid hormones (glucocorticoids, aldosterone, sex steroids) c) Thyroid hormone d) Xenobiotic Ligands (Carcinogenesis)

Receptors
Biological Recognition Unit - Membrane receptors, enzymes, DNA, cytosolic proteins, ion channels - 7-TMS receptors (800-1000); 650 genes, activated by 70 ligands. Target for half of all prescription drugs - ~500 therapeutic targets ( potential 5000-10000 targets) + Effect Magnitude of Effect Type of Effect Concentration- # molecules/volume Efficacy Potency Occupancy Equation D+R DR (mass action) DR/RT = D/ D+ KD How well a drug binds is based upon the number and strength of intermolecular interactions Rt= R + DR (Conservation of mass)

Kd is inversely related to affinity. Affinty-Unique property of drug- receptor pair. ( Van der Waals, Hydrogen Bonding, Electrostatic Interactions) Group Receptors Accroding to their shared characteristics Membrane Receptors, 7-transmembrane receptor, serotonin receptor, serotonin 1 receptor, serotonin 1B receptor. - Several receptors have similar affinity values- experimental variability. - Multiple drugs are used for receptor classification. - There is a selectivity Window. Radiactive Decay - Rate of decay is constant and unique for each radioisotope- measured in disintegrations per minute. - For individual radioisotope, DPM is proportional to the number of radioactive atoms present. Specific Binding= Total- Non-specific Better Approach= SPECIFC + NON-SPECFIC Scatchard Anaysis- Easily abused Stimulus Response- How well the cell turns the receptor stimulus into a response Allosteric Modulation - Can cause conformational changes from predominant conformation to allosteric conformation. Agonists- Intrinsic Efficacy