L2- agonists and dose response curves

What is an agonist

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

Step of agonist pathway (4)

• agonist binds to receptor

• Agonist receptors compelx forms

• Action

• Effect

Example of an agonist and its pathway (4)

• salbutamol

• Binds to b2-adrenorecptor complex

• Increase cAMP levels

• Causes bronchodilation

Are ligands endogenous or exogenous

Can be both

Why is dose important

“All things are poisons it is only the dose that makes it a poison”

Types of dose response curves (2)

Can be concentration vs effect or a semi logarithmic plot of agonist conc vs response

Types of dose response relationships

Graded and quintal

Graded dose response relationships

• show reponse of a particular insinuar system eg isolated tissue, animal or plant

• Measures against agonist conc

Quantal dose relationships

• drug doses eg agonist or antagonist require to produce a specific response determines in each member of a population

On a log graph what does each unit represent

An exponential increase on the previous value

What does a dose reo se cure allow you to estimate (4)

Emax, efficacy, EC50, potency

What is Emax

The concentration at which you see the max response

What is EC50

The concentration required to produced 50% of the max response

What value do you use to determine efficacy

Emax

What value do you use to look at potency

EC50

Affinity

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

In the 2 state hypothesis what shows affinity

R→ AR

In the 2 state hypothesis what shows Efficacy

AR→AR*

Between R and AR of the 2 state hypothesis, what do K1 and K-1 represent

K1= rate of association

K-1 = rate of dissociation

How is receptor saturation measured

by finding the max number of binding sites = Bmax

How to find Bmax

Pltodrug bound against drug conc and Bmax= highest value

How to measure specific binding of the drug

Total-non specific binding

Kd

Equilibrium dissociation constant

What does a high affinity drug has a high tendency to do

Bind to the receptor (large value ofK1) relative to its dissociation from teh recprot (small value to K-1)

How doe Kd change for each recptor/drug combo

Is the same in any tissue in any species

What can Kd be used to ID

An unknown receptor

What can Kd be used to compare

The affinity of different drugs on the same receptor

Under the assumption of a direct relationships between receptor occupancy and reponse what does the Kd tell us

The concentration of ligand at whcih 50% of the available receptors are occupied

What is the relationship between Kd and affinity

Inverse

What does a low Kd indicate

A higher affinity therefore a tighter ligand receptor interaction

Potency

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

What is potency dependent on (4)

• affinity of drug

• Efficacy of drug

• Receptor density

• Efficiency of stimulus- response mechanisms used

What is the relationship between EC50 and potency

The lower the EC50 value the greater the potency

What is the relationship between potency and high affinity

Agonists with high potency tend to have high affinity

When aaare Kd and EC50 equal

If there is a linear relationship between receptor occupation and biological effect eg 50% receptor occupation would cause 50% effect

When aare systems said to have “spare receptors “

When receptors amplify signal duration and intensity so that only a fraction of total receptors for a specific ligand may need to be occupied to elicit a maximal response from a cell

What does efficacy describe

The ability of an agonist to activate a receptor eg evoke an action at the cellular level

What is efficacy determined by

The nature of the recprot effector system

What does efficacy refer to

The max effect an agonist can produce regardless of dose

When is AR* very likely to be produced and why

With a full agonist as these aare high efficacy so produce a max response while only occupying a small % of the receptors that are available

When is AR* less likely and why

With a partial agonist as there are low efficacy so are unable to produce a max response even when occupying all the available receptors

With a full agonist what does the max response produced correspond to

the max response that the tissue can give

What is a partial agonist

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

Examples of partial agonists and their roles (3)

• varenicline= nicotine receptor partial agonist for smoking cessation

• Tamoxifen= estrógeno receptor partial agonists for use in estrógeno dependent breast cancer

• Aripiprazole= partial agonists at selected dopamine receptors

What do inverse agonists have a higher affinity for

The AR(inactive) state than the AR*(active) state

Which classical competeitive antagonists display inverse agonist acitivty (3)

• cimetidine (H2)

• Pirenzepine (M2)

• Atropine (M)

What % of competitive antagonists are actually inverse agonists

85%

What would happen with a neutral antagonist on its own

No response should be elicited

What benzodiazepine acting on the GABAa receptor an example of

An allosteric modulator

What happens when BZ binds to the allosterically site on teh GABAa receptor

prolonged and greater decrease in membrane potential due to more Cl- channels opening

What effect on Ka and effeciacy of GABA does BZ have

Increases KA fro GABAa and increases efficacy of GABAa

When are positive allosteric modulators active and what are 3 examples

They rent active along but increase the affinity and or efficacy coa endogenous agonist

• diazepam

• Propofol

• ISO fluirá e

When are negative I allosteric modulators active and what are is an example

They aren’t active alone but decrease the affinity and or efficacy of endogenous agonists

• mGluR5 dipraglurant

Which type of allosterical modulator is used clinically and which is used more for research

PAM- clinically

NAM- research

What happens with desentisaiton of receptors

The effect of the drug reduces with continual/ repeated administration

What is desensitisation of receptors called

Tachyphylaxis

What are the contributing factors to the desensitisation of receptors (5)

• conformational changes in receptors → drug wont bind as it did before

• Internalisation of receptors → means a higher dose is needed than before

• Depletion of mediator

• Altered drug metabolism → may change how much drug is avaibale

• Other physiological reasons eg homeostatic → the body wil try to offset some of the effects of the drug