Pharm 3 - Receptor Binding: Agonist & Antagonists

Dose-Response Curve in Presence of Noncompetitive irreversible Antagonist

Irreversible antagonist shifts the dose-response curve downward Reduces efficacy of agonist (*Decrease Emax*) - No change in potency - Insurmountable: Effects of an irreversible antagonist cannot be overcome by increasing concentration of agonist Antagonist binds and removes receptors from the pool, decreasing the amount of available receptors for the agonist to bind and thus decreasing the max effect.

Summary of Allosteric Modulator Action

KNOW THIS Summary of Allosteric Modulator Action

Summary of Receptor Antagonist Action

KNOW THIS Summary of Receptor Antagonist Action

Efficacy (Emax)

Maximal effect a drug can produce.

Reversible Drug-Receptor Interactions are...

Noncovalent and Electrostatic Ionic Hydrogen Hydrophobic Van der Waals

Chantix (Varenicline)

Partial agonist at receptors in the brain for nicotine - activates nicotine receptor (with lower effect than nicotine) - reduces addictive effects of nicotine

Graded *Dose-Binding* Curve

Plot fraction of receptors bound against drug dose (log scale) *Kd* = drug concentration required to bind 50% of total receptor - *Smaller the Kd, Greater the Affinity*

Full Agonists

Produce the maximal effect i.e. morphine, oxycodone, codeine - Full agonist always has higher efficacy than partial agonist

Inverse Agonists

Reduce the low level of constitutive/basal activity observed in the absence of any agonist

Agonist

*Activator* Any drug/chemical molecule that binds a receptor and *produces an effect*

Dose-Response vs Dose-Binding

*EC50 = Kd* because: Maximum effect achieved when all receptors are bound. Magnitude of the drug effect is proportional to amount of drug-receptor complexes.

Emax

*Efficacy*

Antagonist

*Inhibitor* Any drug/chemical molecule that *blocks the effect of an agonist*

Drug-Receptor Interactions

*Irreversible:* Covalent *Reversible:* Ionic Hydrogen Hydrophobic Van der Waals

Chemical Antagonist: 2 Examples

*Protamine sulfate*: stably binds to heparin and reverses anti-coagulant effects *Dimercaprol*: binds to toxic metals which are then excreted in the urine

*Competitive and Reversible* Antagonists

- Agonist and antagonist bind to active site on same receptor. - Antagonist competes with agonist for binding to receptor. - Binding of antagonist to the receptor is reversible. - Antagonist binding does NOT activate the receptor (just blocks it)

Example of Physiological Antagonism

- Glucocorticoids can lead to increased blood sugar - Insulin acts at the insulin receptor to decrease blood sugar levels - Clinicians sometimes administer insulin to oppose the hyperglycemic effects of elevated glucocorticoid levels (higher glucocorticoid levels due to increased synthesis from tumor in adrenal cortex or glucocorticoid therapy)

Affinity

- Measure of the ability of the drug to bind its receptor site - Drugs with a higher affinity usually are more potent

Magnitude of a Drug Effect is Proportional to...

...the amount of drug:receptor complexes formed. Maximum effect is achieved when all receptors are bound by drug.

Receptor Conformations and Drug Interactions

2 Receptor Conformations - *Ri* = inactive form that produces no effect when bound by agonist (also no effect when unbound) - *Ra* = active form that produces a small effect in absence of bound agonist and a much larger effect when bound by an agonist - Ra low-level activity in absence of agonist is what Inverse Agonists diminish

Dose-Response Curves for Different Allosteric Modulators

A = Agonist Alone B = Negative (Affinity) C = Positive (Activation) D = Negative (Activation) E = Positive (Affinity)

Possible Dose-Response Curves

A alone = Agonist alone Which curve represents addition of an allosteric antagonist? A+D What was possibly added to produce curve A + B? Reversible Competitive

Partial Agonists have Antagonist Activity

A and B bind to the same site on the receptor A = full agonist B = partial agonist/partial antagonist Partial Agonist competes with a Full Agonist for binding on the receptor, but a Partial agonist cannot produce as great of an effect as a Full agonist. Thus, when a partial and full agonist are both present, the partial agonist has antagonistic activity (against the full agonist), reducing the effect.

Receptor Antagonists

Act on the same receptor as the agonist Active Site Binding - Reversible = *Competitive Antagonist* - Irreversible = *Noncompetitive Active Site Antagonist* Alloesteric Binding - Reversible and Irreversible = *Noncompetitive Allosteric Antagonist*

Physiological Antagonist (Non-Receptor Antagonists)

Agonist (A) and Antagonist (B) bind 2 different receptors (RA and RB) - Activation of the two receptors (by binding their agonists) produces opposing physiological effects - B is the physiological antagonist for RA - B is the agonist for RB

Antagonist Classification - 2 main groups

Agonists either act on the same receptor (active site) as the agonist (*Receptor Antagonists*), or not on the same receptor (*Nonreceptor antagonists*).

Modulating Activation

Always affects the *level of response* Dose-response curve moves *up or down* Changes *Efficacy*

*Noncompetitive Allosteric* Antagonist

Antagonist binds to receptor at site different from agonist. - Blocks the responsiveness of the receptor to agonist - Prevents binding of agonist to active site of receptor OR - Prevents activation of the receptor after agonist binds *looks like an irreversible antagonist on dose-response curve*

Potency

Indication of the amount of drug needed to produce a given effect - Defined by the EC50 - *Smaller the EC50, greater the potency*

Allosteric Modulators

Bind to a site on the receptor that is different from the agonist binding site - Alter the *affinity* of the agonist for the receptor OR the level of receptor *activation* after agonist binding -->*Increase : Positive allosteric modulator* --> *Decrease : Negative allosteric modulator*

"Lock and Key" Analogy for Receptor Binding

Binding "unlocks" the cell's response and causes a change in the cell. - Agonist is a drug that mimics a natural molecule. These drugs "pick the lock." - Antagonist is a drug that prevents the natural molecule from causing a response in the cell. These drugs "jam the lock."

*Noncompetitive and Irreversible* Receptor Antagonist

Binds irreversibly/covalently to active site of receptor - Antagonist binding reduces the total number of receptors available for agonist to bind

Partial Agonists

Cannot produce the maximal effect even when all receptors are bound - Always has lower efficacy than full agonist i.e. buprenorphine (Subutex)

Dose-Response Curve in Presence of Competitive Antagonist

Competitive antagonist shifts dose-response curve to the right - Decreases potency of agonist (Increase EC50) - No change in efficacy (Emax) - Surmountable: Effects of competitive antagonist CAN be overcome by increasing agonist concentration

Nonreceptor Antagonists

Do not act on the same receptor as agonist - Chemical Antagonist - Physiological Antagonist

Chemical Antagonist (Non-Receptor Antagonists)

Do not interact with a receptor (Receptor Independent) - Interact directly with the drug/agonist - Remove the drug from the system OR - Prevent the drug from binding to its receptor Examples: *Protamine sulfate*: stably binds to heparin and reverses anti-coagulant effects *Dimercaprol*: binds to toxic metals which are then excreted in the urine

Modulating Affinity

Dose-response curve moves *left or right* Changes *Potency*

Efficacy Graph

Drug X<Y=Z

Potency Graph

Drug X>Y>Z

Types of Agonists

Full Agonists Partial Agonists Inverse Agonists

Allosteric Modulators of GABA_A Receptor

GABA_A (gamma-aminobutyric acid type A) receptor Chloride ion channel expressed on neurons that inhibits neuron function when activated. Important for neural activity modulation Positive modulators make receptor more responsive to GABBA (--> increased neuron inhibtion) - Propofol, midazolam, etc.

Graded *Dose-Response* Curves

Illustrate the relationship between concentration of drug and the drug effect or response

Efficacy vs Potency - Which is the better drug to Prescribe?

X vs Y - it depends on how much of an effect you desire Y vs Z - both are equally efficacious, but Y achieves the same effect with a lower dose and thus is the better choice (limits toxicity)

[Drug] + [Receptor] ---> [Drug:Receptor complex]

[Drug:Receptor complex] --> --> --> Drug effect

Dimercaprol

binds to toxic metals which are then excreted in the urine

Kd

drug concentration required to bind 50% of total receptor - Smaller the Kd, greater the affinity (inverse)

EC50

drug concentration that produces 50% of the maximal effect

*Antagonist*: Drug-Receptor Interactions

equal affinity for Ra and Ri - binds to receptors in both conformations, but has no DIRECT effect on the receptor itself. Rather, it blocks the receptor so that the agonist cannot bind. - Ra bound to an antagonist will still have a low-level effect, as it would unbound

*Full Agonist*: Drug-Receptor Interactions

much higher *affinity for Ra* than for Ri - Ra binds agonist (D) and becomes Ra-D, to maintain equilibrium Ri then becomes Ra, which can bind the agonist - as more agonist is added, more recceptors become bound and produce an effect - in this way all of the inactive receptors can be converted to active and then bound --> enables reaching Maximum Effect

*Inverse Agonist*: Drug-Receptor Interactions

much higher affinity for Ri than for Ra - this pulls the equilibrium towards Ri until all receptors are in the inactive form

*Partial Agonist*: Drug-Receptor Interactions

somewhat higher affinity for Ra than for Ri, but can bind to both - can never get 100% binding to active receptor due to some binding to Ri

Protamine sulfate

stably binds to heparin and reverses anti-coagulant effects