Basic receptors

• Drug target


  Four main kinds of regulatory proteins commonly involved as primary drug targets: Receptors, Enzymes, Carrier molecules (transporters), Ion channels
• Receptor


  • (to a neuroscientist) A protein that binds a neurotransmitter/modulator
  • (to a cell biologist or biochemist) A protein that binds a small molecule, A protein that binds another protein, A nucleic acid that binds a protein
  • (to a toxicologist) A macromolecule that binds a toxicant
  • (to a pharmacologist) A target molecule through which soluble physiological mediators produce their effect

  
• Drug-Receptor Interactions


  1. Ligand + Receptor

  2. Ligand-Receptor Complex

  3. Response(s)
• Main receptor classes


  • Minutes, Seconds, Hours, Hours
• The vast majority of drugs show a remarkably high correlation of structure and specificity to produce pharmacological effects
• Experimental evidence indicates that drugs interact with receptor sites localized in macromolecules which have protein-like properties and specific three dimensional shapes

  
• A minimum three point attachment of a drug to a receptor site is required
• In most cases a rather specific chemical structure is required
• Slight changes in the molecular structure of the drug may drastically change specificity (no drugs are completely specific in their action!!!)
• Several chemical forces may result in a temporary binding of the drug to the receptor
• Covalent bonds would be very tight and practically irreversible. Since by definition the drug-receptor interaction is reversible, covalent bond formation is rather rare except in a rather toxic situation
• Aims of binding studies on pharmacological receptors


  • Obtain reliable estimates of the affinities of selected ligands for the receptor of interest together with their associated errors
  • Analyse the mechanism of interaction of ligands with the receptor alone, and in combination

  
• Binding studies


  Kinetic experiments, Saturation experiments, Competition/modulation experiments
• Radioreceptor Assay


  To measure the binding of drugs to receptors
• Agonist


  A substance that interacts with a specific cellular constituent, the receptor, and elicits an observable Biological response. It may be endogenous or exogenous substance
• Partial agonist


  Acts on the same receptor as agonists, however, regardless of its dose it cannot produce the same maximal biological response as a full agonist

  
• Inverse agonist "negative antagonist"


  It acts on the same receptor of the agonist yet produces an inverse effect
• Spare receptor


  Maximal responses are elicited at less than maximal receptor occupancy. A certain number of receptors are "spare." Spare receptors are receptors which exist in excess of those required to produce a full effect. There is nothing different about spare receptors. They are not hidden or in any way different from other receptors
• Intrinsic activity


  A proportionality constant of the ability of the agonist to activate the receptor as compared to the maximally active compound in the series being studied

  
• Antagonist


  Inhibits the effect of an agonist but has no biological activity of its own. It may compete on the same receptor site that the agonist occupies or it may act on allosteric site
• Types of antagonists


  • Competitive: Antagonist binds to same site as agonist in a reversible manner
  • Noncompetitive: Antagonist binds to the same site as agonist irreversibly
  • Allosteric: Antagonist and agonist bind to different site on same receptor
  • Physiologic: Two drugs have opposite effects through differing mechanisms
• Heteroreceptor


  A receptor that regulates the synthesis and/or the release of chemical mediators other than its own ligand
• Autoreceptor


  A macromolecule typically found in the nerve ending that regulates the synthesis and/or the release of its own ligand
• Receptor down-regulation


  A phenomenon whereby an agonist, actually induces a decrease in the number of those receptors available for binding
• Receptor up-regulation


  A phenomenon whereby an agonist, actually induces an increase in the number of those receptors available for binding
• Affinity


  The ability of a drug to combine with a receptor; it is proportional to the binding equilibrium constant KD. A ligand of low affinity requires a higher concentration to produce the same effect. Both agonists and antagonists have affinity to the receptor
• Efficacy


  A measure of the biochemical or physiological effect which results, following the binding of a drug to its target. Efficacy is a measure of the maximum effect the drug can produce
• Potency


  Refers to the dose of a drug required to produce a specific effect of given magnitude (usually 50% of the maximum effect) as compared to a standard reference. Potency is dependent upon both affinity and efficacy

  
• Ligand


  Substances, molecules or compounds which bind with receptors present in the body e.g., acetyl choline, adrenaline, noradrenalin, neurotransmitters like glutamate, aspartate and GABA. They produce various effects and interfere with the flow of ions through channels called ligand gated channels
• Agonist


  Drugs which when bind receptors, cause activation of receptors. They have the capacity to produce chain reactions in the receptors which ultimately bring about the effects. Agonists have two properties: Affinity for receptor, Capability to produce chain reactions in the cells having capability of intrinsic activity or efficacy
• It is important to distinguish between actions of drugs and their effects. Actions of drugs are the biochemical physiological mechanisms by which the chemical produces a response in living organisms. The effect is the observable consequence of a drug action
• For example, the action of penicillin is to interfere with cell wall synthesis in bacteria and the effect is the death of the bacteria