Drug TargetsDrug[A]-Receptor[R] complex[AR] regulates cellular functionQuantum (All or None) ResponseTherapeutic IndexGraded Dose-Response CurveDrug TargetsBroadly defined as any target molecule with which a drug* molecule combine and elicit specific effect *Same applies to a physiological ligand A more specific, pharmacological definition applies to a macromolecule that serves as a recognition site for a chemical agent (ligand) and mediates the action of the ligand Many receptors are expressed on cell surface, but some are present inside the cell (e.g. nuclear receptors)For a molecule to qualify as a receptor, it must meet 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)Kd = (Equilibrium) Dissociation constant (unit:M) fb![D]!Kd + [D]!=! Low Kd = high affinity = difficult to dissociate, nM to pM High Kd = low affinity = quick to dissociate, mM to µM R + D RD Effect!k1!k2!k3!Kd = k2/k1Dose-Response Curve Occupational Theory of Drug action In occupational theory of drug action, fraction of receptor binding is equal to the fraction of max effect. However, it was demonstrated later that the occupational theory does not work in most of cases.Response is not proportional to the fraction of receptor occupancy. 1. Signal is amplified at the receptor. 2. The concept of “spare receptors”. (100 % binding is not necessary to generate max response)Potency and EfficacyPotency and Efficacy are independent.Agonist and AntagonistAntagonist: Competitive or NoncompetitivePartial AgonistQuestion: Draw a dose-response curve of a partial agonist in the presence of a fixed amount of full agonist?Inverse Agonist Allosteric Theory of Drug actionAllosteric Theory (two state theory) of drug actionResponse is amplified at the
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