Week 6 Receptor theory

receptor

specific macromolecular component of a cell with which a drug interacts to initiate its biochemical and physiologic effects

receptor defined by 2 properties

recognition (selective binding of a ligand)

transduction (conversion of binding into a cellular signal)

receptor binding

usually reversible and governed by chemical forces: ionic, hydrogen, hydrophobic, van der Waals; covalent binding gives long-lasting effects

Macromolecules that act as Drug Targets

Regulatory proteins, Enzymes, Transport proteins, Structural proteins, Nucleic acids

4 consequences of receptors

Quantitative relationships

Therapeutic selectivity

Agonists vs. antagonists

Drug discovery

affinity

how tightly a drug binds to its receptor

Kd

concentration occupying 50% of receptors

measures affinity

high affinity and zero efficacy

antagonist

efficacy

how much effect the bound drug produces

intrinsic activity: full agonist>partial agonist>antagonist

zero efficacy

antagonist

selectivity

how narrowly the drug acts on one receptor

always dose dependent

affinity (Kd) and efficacy

are independent

5 receptor superfamilies

Ligand-gated ion channels - milliseconds (fastest)

G protein-coupled receptors (GPCRs) - seconds

Enzyme-linked receptors - minutes

Cytokine receptors (JAK/STAT) - minutes

Intracellular/nuclear receptors - hours

Drug selectivity

drug's ability to bind preferentially to certain receptors over others, 3D structure of a receptor determines which drugs can bind to

Small changes in drug structure

can produce large changes in affinity, the basis of structure-activity relationships

Stereoselectivity

Receptors may bind one enantiomer more strongly than another

S-warfarin is more potent than R-warfarin

Receptor subtypes

allow medications to target specific receptors and produce more targeted effects, potentially reducing unwanted effects in other tissues

Receptor Regulation

can change due to disease or long-term drug exposure in expression, coupling, and localization

Expression

Number of receptors present

Coupling

How receptors communicate with intracellular signaling systems

Localization

Where receptors are located in the cell

Different beta-receptor subtypes

are located in different tissues and produce different effects when activated

b-1 heart, b-2 airway, b-3 adipose

propranolol nonselective block

blocks beta-1 and bet-2 so the blood pressure benefit arrives with airway risk

difference b/t B1 and B2 receptors

B1 receptor requires a catechol ring, where bulk at N-substituent is allowed for B2 activity and decreases B1 receptor activity

conversion of agonist to antagonist

changing a drugs chemical structure can change it from an agonist to an antagonist

β1 Receptor Antagonism

replacement of catechol ring with a para substituted phenyl ring provides antagonist activity

Occupancy Theory (A. V. Hill)

amount of drug binding to receptors depends on the drug's concentration

low Kd = high affinity

Occupancy Theory graph curve

sigmoidal (S-shaped) curve because drug concentration is plotted on a logarithmic scale

Receptor Occupancy Theory (A. J. Clark)

assumed drug response is directly proportional to receptor occupancy

sigmoidal curve

EC50

Drug concentration that produces 50% of the maximum effect

lower value=higher potency

Drug Effect graph (hyperbolic)

pharmacodynamics: how much effect does the drug produce

Emax, EC50, X-axis drug conc., Y-axis drug effect

Receptor Binding graph (hyperbolic)

Receptor Occupancy: How many receptors are occupied by the drug

Kd, Bmax, X-axis drug conc., Y axis receptor bound drug (B)

Both receptor binding and drug effect

increase as drug concentration increases, but eventually reach a maximum

Binding Equation

describes how much drug binds to receptors

Effect Equation

describes how much effect a drug produces

Concentration-response curves

Plotting effect against log concentration converts the hyperbola into a symmetric sigmoid curve

Concentration-response curves 0–20%

Drug effect is approximately proportional to concentration

Concentration-response curves 20–80%

Drug effect is approximately linear with the log of concentration

Concentration-response curves 80–100%

The system approaches maximum capacity, so additional drug produces little extra effect

doubling a dose

rarely doubles the effect, can add toxicity w/o adding benefit

Spare receptors

Receptors that do not need to be occupied for a drug to produce its maximum effect (Emax)

Kd is more then EC50

whenever spare receptors are present

effect curve lies to the left of the binding curve

Why Do Spare Receptors Exist

bc of signal amplification and Prolonged signaling

Signal amplification

Activating a small number of receptors can produce a large cellular response

Prolonged signaling

effect may continue even after the drug separates from its receptor, such as when enzymes remain activated

Clinical Consequence of spare receptors

Irreversible antagonists permanently inactivate receptors

Efficacy Spectrum

full agonist, partial agonist, neutral agonist, inverse agonist

Competitive (Reversible) Antagonism

Shifts the agonist concentration-response curve to the right without reducing Emax, assuming surmountable antagonism

effect depends on ratio of antagonist to
agonist

Irreversible antagonist

Can decrease Emax because functional receptors become unavailable

More agonist overcomes

competitive blockade, it does not overcome irreversible blockade
Recovery requires synthesis of new receptors

duration of irreversible antagonists outlasts

the drugs plasma half-life

partial agonist

Occupies all receptors yet cannot produce Emax bc it stabilizes an intermediate active receptor conformation

partial agonist w/ a full agonist

Acts as an antagonist, it competes for the same receptors and reduces the overall response

neutral antagonist w/ full agonist

Rightward shift only (competitive)

inverse agonist w/ full agonist

Blocks agonist and lowers basal tone

Irreversible antagonist w/ full agonist

decreases the maximum effect a drug can produce, depresses Emax

Antagonism That Does Not Involve the Receptor

Chemical Antagonism, Physiologic Antagonism, Allosteric Modulation

Chemical Antagonism

directly binds to another drug or substance and neutralizes or removes it

Physiologic Antagonism

Two agonists act on different receptors to produce opposite physiological effects

Allosteric Modulation

drug binds to a different site on the receptor than the agonist which changes the receptor's affinity or response to the agonist

Constitutive activity

When a receptor produces a signal even without a drug or agonist binding to it

Receptors naturally exist in two states

Ri (Inactive): Receptor is not producing a signal.

Ra (Active): Receptor produces a signal

baseline signaling

some receptors spontaneously switch into the active state

Increases signaling above baseline

Agonist

Does not change baseline signaling

Neutral Antagonist

Decreases signaling below baseline

Inverse Agonist, binds to Ri preferentially