Drug TargetsDrug[A]-Receptor[R] complex[AR] regulates cellular functionQuantum (All or None) ResponseTherapeutic IndexGraded Dose-Response CurveDrug TargetsKd = (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 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 AgonistInverse Agonist Allosteric Theory of Drug actionAllosteric Theory (two state theory) of drug actionResponse 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)Spare Receptors (Receptor Reserve) fb![D]!Kd + [D]!=!Response is not proportional to fb but dependent on fb. In other words, Response is function of fb.Signal transduction pathways in mammalian cells!Pharmacological basis of therapeutics 10th edition!by Goodman & Gilman!!!Four types of receptorMolecular Structure of four types of ReceptorFour types of receptorGPCRs are excellent targets for drug discovery!1. The most widely used signaling mechanism and regulate almost all aspects of physiolgical processes.!2. GPCRs consists of the largest gene family of our genome.!3. Orphan GPCRs and the oligomerization of GPCR provide further opportunities for novel drug development.! Targets of current drugs!Hopkins and Groom, Nat Rev. (2002)!G protein-mediated signal transduction (Most widely used mechanism of receptor-mediated signaling)Mechanism of G protein cycle The amount of GαGTP determines the strength and duration of the signal� Gs !Gsα ! !Adenylyl Cyclase (stimutation) !!!Golfα" !Gi !Gtα1 " "cGMP Phosphodiesterase (stimulation)!!Gtα2"!!!Giα1 " "Adenylyl Cyclase (inhibition)!!Giα2""Giα3"""GoαA ! !Adenylyl Cyclase (inhibition) (?)""GoαB!""Gzα ! !Adenylyl Cyclase (inhibition) !!! Gq !Gqα " "Phospholipase C β (stimulation)""G11α!!G14α!!G15/16α"" G12 !G12α " "RhoGEF (stimulation)!!G13α!" Classification of Gα subunits!Soluble second messengers!Gs and Gi pathway!Beta-adrenergic receptor couples to Gs !!Gq signaling pathway!Gq!Gq stimulates PLCbeta isozymesDesensitization of beta-adrenergic receptor-mediated response.Desensitization of Receptor-mediated responseDesensitization of G protein-mediated signalingLigand gated ion channelGrowth factor receptor with tyrosine kinase
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