L2 Agonists and dose response curves

What is the definition of an agonist

A ligand (drug, hormone or neurotransmitter) that combines with receptors to elicit a cellular response

What are the general functions of an agonist

• Receptor

• Agonist-receptor complex

• Action

• Effect

What are the functions of Salbutamol as an agonist

• Beta 2-adrenoreceptor

• Salbutamol-B2-adrenoreceptor complex

• Increased cAMP

• Bronchodilation

What dose of aspirin is required to relieve a headache?

300-600mg

What is a dose-response curve

• Concentration-effect curve

• Semi-logarithmic plot of agonist concentration against response

What are graded dose-response relationships

• Response of a particular (individual) system

• Isolated tissue, animal, patient

• Measured against agonist concentration

What are quantal dose-response relationships

• Drug doses

• agonist or antagonist

• required to produce a specified response determined in each member of a population

What is a logarithmic axis

There is a 10 fold increase from one unit to the next. Increases exponentially

What shape is a quantal dose response curved compared to graded

Quantal curves increase up to a point and then decrease due to it measuring multiple instances, whereas graded curves increase to an individual

What plot a dose-response curve?

• Allow estimation of Emax

• Allow estimation of conc or dose required to produce 50% of maximum response

• Allow efficacy to be determined

• Allow potency to be determined

What is the definition of affinity

The strength with which an agonist/drug binds to a receptor

What does R stand for

rested state

what does R* stand for

activated state

what is k1

the rate of association of the agonist with the receptor

what is k-1

the rate of AR complex dissociation

what is the equation to find affinity

affinity= k1/k-1

what is Kd

equilibrium dissociation constant

What effect does a high affinity drug have

A greater tendency to bind to the receptor (large value for k1), relative to its dissociation from the receptor (a small value for k-1)

What is Kd the same for

any given receptor and drug combination in any tissue of any species (as long as the receptor is the same)

What can Kd be used to identify

an unknown receptor

What can Kd be used to compare

the affinity of different drugs on the same receptor

What kind of constant is Kd

physiochemical (like Avogadro’s number)

If we assume there is a direct relationship between the receptor occupancy and response, what is the effect on concentration and affinity

• Concentration of ligand at which 50% of the available receptors are occupied

• There is an inverse relationship between Kd and affinity

• Kd= k-1/k1

What does a lower Kd indicate?

a tighter ligand-receptor interaction (higher affinity)

What does affinity describe

the tendency of the ligand to form a stable complex with the receptor

What is affinity determined by

the number/nature of bonds and the ‘level of fit’ between ligand and receptor

What is potency

The amount of drug needed to produce a given effect (50% of Emax)

what does potency depend on

• affinity of the drug

• efficacy of the drug

• receptor density

• efficiency of stimulus-response mechanisms used

What affinity do agonists with high potency have

high affinity

What effect does the EC50 value have on potency

The lower the EC50 value, the greater the potency

In a linear relationship, what is the relationship between Kd and EC50

Kd and EC50 are equal

What do systems with amplified signal duration and receptors have

spare receptors

How can a maximum response be achieved

with only a small fraction of all receptors occupied

What does efficacy describe

the ability of an agonist to activate a receptor

What is efficacy determined by

the nature of the receptor-effector system

What is efficacy

the maximum effect an agonist can produce regardless of dose

What efficacy does a full agonist have

high efficacy - AR* very likely

What efficacy does a partial agonist have

low efficacy - AR* less likely

what is a partial agonist

a ligand that combines with receptors to elicit a maximal response which falls short of the maximal response the system is capable of producing

What is the partial agonist Varenicline

nicotine receptor partial agonist for smoking cessation

What is the partial agonist tamoxifen

Estrogen receptor partial agonists for use in estrogen dependent breast cancer

What is the partial agonist aripiprazole

Antipsychotic -partial agonists at selected dopamine receptors

What are inverse agonists

They have higher affinity for the AR (inactive) state than for the AR* (active)

What percentage of competitive agonists are actually inverse agonists

~85%

What is an example of an inverse agonist

Beta-carbolines on GABA A receptors - anxiogenic rather than anxiolytic

What are positive allosteric modulators (PAM)

Not active alone but increase affinity and/or efficacy of endogenous agonists

Give 3 examples of PAM

• Diazepam

• Propofol

• Isoflurane

What are negative allosteric modulators

Not active alone but decrease affinity and/or efficacy of endogenous agonists

Give an example of a NAM

mGluR5 dipraglurant ???

Descibe tacyphylaxis

Effect of the drug reduces with continual/repeated administration. Desensitisation of receptors

What are the 5 contributing factors of tachyphylaxis

• Conformational changes in receptor

• Internalisation of receptors

• Depletion of mediators

• Altered drug metabolism

• Other physiological responses (homeostatic)