Ligand-receptor model of drug action

1
Ligand-receptor model of drug action

• Objectives Drug action occurs via alteration of
  human or microorganism biochemistry.  This action
  can be modeled in a variety of ways.  Upon
  completion of this lecture the student will be
  aware of the various models of drug action along
  with classification of physiological receptors
  and examples of biological assays of drug action.

2
Contrast pharmacological approach vs. chemical
approach of drug action
3
Drug Interaction Ligand-Macromolecule Complex

• mobile drug cellular receptor --gt drug-receptor
  complex
• Drug specificity based on structural
  complimentarity
• Beyond specific recognition
• agonist
• partial agonist
• antagonist
• inverse agonist

4
Quantitative representations of binding or
activity

• IC50
• EC50
• LD50 or TD50
• Therapeutic index LD50/EC50 or LD50/IC50
• Note that various values may be used subscript.

5
Drug Receptor Theories

• Occupancy Theory affinity versus activity
• Rate Theory agonist versus antagonist
• Induced-Fit Theory conformational changes in
  receptors
• Macromolecular Perturbation Theory
• Activation-Aggregation Theory R vs. T state
• Receptor dimers or dimerization

6
Classification of Receptors

• Receptor versus acceptor
• Pharmacologic
• Biochemical or Biophysical
• Molecular or Structural Classification
• Anatomic Location
• Cellular Location

7
Measurement of Pharmacological ActivityNicotinic
and muscarinic cholinergic receptors
8
Acetylcholine intramolecular distance B as a
function of the central dihedral angle
9
Diagram of nictitating membrane innervation
10
Diagram of nictitating innervation
11
Structure-activity relationship (SAR)

• Structure of polymethylenebismethionium and
  biological activity as a function of the number
  of methylene groups, (CH2)n, separating the
  terminal tetramethylammonium groups.

12
Binding versus activity

• The above assays measure the activity, however,
  different compounds can bind but illicit
  different responses agonist, partial agonist and
  antagonist.
•  Need to measure binding directly.