Toews: Receptors Flashcards
Agonist?
Activates receptors
Antagonist?
Drugs that block receptors. Efficacy=0
Ligand?
All molecules that bind to receptors.
Cellular and Molecular properties of receptors
All proteins. Can be located on cell surface or inside cel. Different cells and tissues express different receptors. Exhibit specificity for which molecules they bind.
Enzymes
Many drugs target enzymes, usually as inhibitors. Can target human enzymes (ex: ACE inhibitor). Many drugs target microbial or viral enzymes.
Ion channels and transporters
Targets for many drugs, usually as channel blockers or transport inhibitors. Ex: diuretics
Ligand-gated ion channel (LGIC) receptor
Ex: Nicotinic receptor for acetylcholine.
On Cell surface membrane.
5 subunits w/ 4 transmembrane domains each
Agonist binds, opens Na+ channels.
Take milliseconds.
Muscle contraction and neurotransmission
G protein-coupled receptors (GPCRs)
Ex: beta-2 adrenergic receptor for epi, NE.
On cel surface membrane.
7 transmembrane domains.
Agonist binds, activation of GTP-binding proteins, and these regulate effector enzymes such as cAMP (Second messengers).
Effects within seconds to minutes.
Regulate metabolism, secretion, cell migration, etc.
Targets for >.5 of prescriptions.
Receptors with intrinsic enzyme activity
Ex: Insulin receptor
On cell surface membrane.
Dimer of single transmembrane domain subunits.
Agonist binds extracellularly, activates enzymatic activity of intrcellular domain; for insulinnreceptor and many others, the enzyme is a protein tyrosine kinase; often called “tyrosine kinase” receptors or “growth factor” receptors.
Initial effects within minutes; many important cellular and physiologic effects mediated by transcription pathways, leading to effects for hours.
Effects gene expression, cell proliferation and differentiation.
Nuclear transcription factor receptors
Ex: Estrogen receptor and other steroid hormone receptors.
In cell cytosol or nucleus.
Dimer of cystolic soluble proteins.
Agonist binds to 1 domain of receptor to activate transcription factor activity on another domain.
Occurs over hours or days.
Effects gene expression, cell proliferation, differentiation, death, and devp. changes.
Receptor binding properties
A. Binding of drugs is reversible (Law of Mass Action). R+D RD
B. Reches “equilibrium” or “steady state” when rate at which drug molecules leave receptor (Dissoc.) equals rate at which new drug molecules bind (Assoc.) Kon[R][D]=Koff[RD]
C. Kd is the equilibrium dissociation constant. It is an equilibrium constant, not a rate constant like Koff and Kon. Kd=Koff/Kon=[R][D]/[RD].
Kd is defined for dissociation in both def.
D. There is a finite number of receptors (Rt) each of which is either bound (RD) or free (R).
Rt=[R]+[RD} Increase drugs saturates receptors.
Fractional receptor occupancy (FRO) =[RD}/[Rt]
E. Combining Equations:
FRO= [RD]/[Rt]= [D]/Kd+[D]
Receptor Binding Plots
- Binding of drug on x-axis. Fractional receptor occupancy on Y-axis. Generates “hyperbolic” binding curve.
- Concentration of drug that occupies 50% of receptors is Kd value.
Affinity
Refers to amt. of drug required to BIND to the receptor. Low Kd indicates high affinity and vice versa.
EC50
Concentration of drug that gives half-maximal effect.
E/Emax~ [D]/ EC50 + [D]
Potency
Amt. of drug required to generate a given fractional response. Low EC50 value indicates more potent drug and vice versa.
Drug-receptor action/effect plots
Drug concentration on log scale on X-axis. Receptor effect on y-axis. Generates sigmoid curve.
- 50% response at EC50, 9% at 1/10 of Ec50, 91% at 10x EC50.
- Half logs are at .3, 3, 30 etc.
- Review Handout pg. 8 & 9 for visuals
Milli-
-3
Micro
-6
Nano
-9
Pico
-12
Femto
-15
Signal Amplification
Because of signal amplification by downstream receptor signal pathways, full receptor occupancy by agonists is seldom required for maximal responses; this leads to the terms spare receptors or receptor reserve
Spare Receptors
The CONCEPT that allows cells to respond to very low concentrations of endogenous mediators or drugs. Mathmatically, EC50 is often lower value than Kd. Potency for response is usually higher than affinity.
Competitive Antagonists
These drugs bind to the receptor in such a way that they prevent other drugs from binding. This increases the apparent Ka and EC50 value for the agonist by a factor of 1+([B]/Kb)
-Competitiv antagonists also reduce the response to a fixed concentration of agonist. The half maximal inhibitory concentration is called IC50. The IC50 will be larger than the true Kb for the antagonist by a factor 1+([A]/Ka).
Affinity
How much drug it takes to bind to the receptor; measured by Kd.
Potency
How much drug it takes to mediate its effect; measured by EC50.
Efficacy
The pharmacological term for how much a drug activates its receptor when it is bound. Defines receptor activation, NOT clinical effectiveness.
Full Agonists
Fully activate the receptor have an efficacy of 1.0
Partial Agonists
Drugs that give less than maximal response, even with full receptor occupancy. Efficacy >0 but less than 1. Partial Antagonist as well.
Subtypes
Multiple receptors for same endogenous ligands.
Desensitization
Decrease in receptor function (effect).
Mechanisms: Covalent modification of receptors, receptor internalization or endocytosis.
Down-regulation
Decrease in receptor number (expression).
Mechanism: Receptor protein degradation
