2015 PMY 311 Lecture 4_student - Learning Objectives...

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Learning Objectives & Knowledge Points By the end of lecture you should: Be able to explain how different ligands (e.g., agonist and inverse agonists) alter the energy landscape Be able to discuss the different conformational changes in the receptor caused by agonists, partial agonists and inverse agonists Be able to explain the difference between the induced fit and conformation selection models of receptor activation Be able to explain ligand bias (i.e., agonist-directed trafficking) Be able to discuss the factors that cause variability in drug responding Be able to discuss how differences in an individual’s genetic make - up (i.e., pharmacogenetics) alters the response to a drug
Learning Objectives & Knowledge Points At the end of this lecture you should: Be able to explain the difference between a graded and quantal dose-response plot Be able to explain how a quantal (population) dose-response plot is generated Be able to discuss how quantal dose-response plots are affected by changes in ADME Be able to discuss how drugs have multiple dose-response plots (e.g., therapeutic, adverse, toxic, lethal) and how adverse effects (i.e., side effects) occur. Be able to calculate the therapeutic index and certain safety factor. Be able to discuss how the population variability affects the quantal dose-response plot and estimates of drug safety.
Ligand binding & Receptor activation Ligand binding → conformational changes in the receptor resulting in different receptor states
Cys265 of β -2 adrenergic receptor labeled with environmentally sensitive fluorophore Ghanouni P et al. J. Biol. Chem. 276:24433-24436 (2001) Agonist binding is associated with a conformational change (e.g. β -2 adrenergic receptor) ISO {(-)isoproterenol}: full agonist ALP {(-)alprenolol}: antagonist
Partial & Full agonists are associated with different sets of receptor conformations Ghanouni P et al. J. Biol. Chem. 276:24433-24436 (2001) β -2 adrenergic receptor ligands: ISO (isoproterenol): full agonist SAL (salbutamol): partial agonist DOB (dobutamine): partial agonist