AFFINITY & ANTAGONISM

Inverse agonist REF: Goodman and Gillman 11^th edition page 14-15, http://en.wikipedia.org/wiki/Inverse_ agonist

Indirect repeat from June 2008

• An inverse agonist is an agent that binds to the same receptor as an agonist but induces a pharmacological response opposite to that agonist.
• A neutral antagonist has no activity in the absence of an agonist or inverse agonist but can block the activity of either
• An agonist increases the activity of a receptor above its basal level while an inverse agonist decreases the activity below the basal level.
• A partial agonist binds to the receptor and causes action submaximal to that of agonist

Inverse agonist activates a receptor to produce an effect in the opposite direction to that of an agonist.

It has high affinity for the receptor, but intrinsic activity with a minus sign.

An inverse agonist is an agent that binds to the same receptor as an agonist for that receptor but produces the opposite pharmacological effect.
Full or complete agonists produce complete activation of a receptor at high drug concentrations.

Partial Agonists produce weaker activation of the receptor than full agonists.
A neutral antagonist is the antagonist without intrinsic activity which displays equal affinity for the active and inactive conformations of the receptor and does not interfere with the basal activity of the cell.

Ref: Applied Pharmacology By Stan K. Bardal, Jason Waechter, Jason E. Waechter, Douglas S Martin, 2010, Page 5; Goodman and Gillman, 11th edition, Page 14-15.

Ans. is ‘a’ i.e., Drug X will be available more in tissues

Highly plasma protein bound drugs are largely restricted to the vascular compartment, So drug Y will remain in the vascular compartment and drug X will available more in tissues.

Ans. is ‘b’ i.e., Binds to receptor and causes opposite action

Agonist                        –>      Have both affinity and maximal intrinsic activity.

Antagonist                  —->           Have affinity but no intrinsic activity.

Partial agonist              –>      Have affinity and submaximal intrinsic activity.

Inverse agonist            —>         Have affinity but opposite intrinsic activity ie intrinsic activity with a minus sign.

Ans. is ‘c’ i.e., Inverse agonist

Ans. is ‘b’ i.e., Has affinity as well as intrinsic activity

Ans. is ‘a’ i.e., Active receptor

Drug-receptor binding and agonism

o A receptor can exist in two conformational states:

(i)               Active state (Ra)

(ii)            Inactive state (Ri)

o Usually, inactive state predominates in the absence of drug and the basal signal output will be low.

o The extent to which the equilibrium is shifted toward the active state is determined by the relative affinity of the drug for the two conformations.

o Agonist  has higher affinity for the active confirmation and drives the equilibrium to the active state and thereby activate the receptor. A full agonist is sufficiently selective for the active confirmation that at a saturating concentration it will drive the receptor essentially completely to active state -3 maximum activity can be produced by agonist.

o Partial agonist  has only moderately higher affinity for the active confirmation (Ra) than inactive confirmation (Ri). Its effect will be less, even at saturating concentrations, so partial agonist cannot produce a full biological response at any concentration —> partial agonist has submaximal intrinsic activity.

o Antagonist has equal affinity for both active (Ra) and inactive (Ri) confirmation. So, antagonist will not alter the equilibrium between Ra & Ri, and will not produce an effect —> antagonist has no intrinsic activity.

o Inverse agonist  has greater affinity for inactive confirmation (Ri) and drives the equilibrium to the inactive state. So, inverse agonist has an effect opposite to that of an agonist —> inverse agonist has intrinsic activity with a minus sign that means opposite intrinsic activity. Examples of such inverse agonists at G-protein coupled receptors are

Famotidine, losartan, metoprolol and risperidone.

1.   Agonist has affinity for active configuration (Ra)

2.     Partial agonist has affinity for bath active (Ra) as well as inactive (Ri) confirmation, but has more affinity for active configuration (Ra > Ri)

3.     Antagonist has equal affinity for active and inactive confirmation (Ra = Ri)

4.     Inverse agonist has affinity for inactive confirmation (Ri)

Ans. is ‘b’ i.e., An inverse agonist has a higher affinity for the active form of receptor as compared to the inactive form

o An inverse agonist has higher affinity for inactive confirmation (Ri) of receptor and will produce an effect opposite to that of an agonist; examples of such inverse agonists at G-protein coupled receptors are famotidine, losarton, metoprolol, risperidone.

For option a & c you should know the following important facts:

o As I have explained in previous explanation; usually inactive confirmation (Ri) of receptor predominate in the absence of agonist and the signal output is low. If the preexisting or basal equilibrium for unliganded receptors lies far_.in the direction of inactive confirmation (Ri), it may be very difficult to demonstrate inverse agonism because receptors are already existing in inactive state and inverse agonist has nothing to do (inverse agonist shifts the equilibrium towards inactive confirmation, but the receptors are already existing in inactive confirmation).

o Some times receptor can adopt active confirmation (in the absence of agonist) that can produce a cellular response spontaneously -3 constitutional spontaneous activity without an agonist. In this situation, the tissue behaves as if there were agonist present. In this situation.

i)           Inverse agonism can be easily observed as inverse agonist shifts the equilibrium towards inactive state. So, it inhibits the agonist-independent constitutional signaling which can be easily observed.

ii)         Antagonist will have no effect as antagonist has equal affinity for active (Ra) as well as inactive (Ri) state of receptor. So, the equilibrium will remain the same.

iii)       It will be difficult to demonstrate activity of agonist as agonist shifts the equilibrium towards active confirmation, but the receptors are already existing in active confirmation (constitutional spontaneous active state).

o Now you can easily understand:

A. In usual resting stage (when inactive confirmation of receptor predominates in the absence of agonist)

i)        Agonism can be observed easily

ii)      Antagonism can be observed easily

Inverse agonism is difficult to observe

B. In stage of spontaneous constitutional activity when active confirmation predominates in the absence of agonist (It may sometime occurs due to rnutation –*constitutively active mutant receptors)

i)           Agonism is difficult to observe

ii)      Antagonist has no effect

Inverse agonism can be observed easily

Ans. is ‘d’ i.e., Adrenaline and histamine

Physiolo^gical antagonists

o Physiological antagonists are those that produce opposite action by acting on different receptors.  Example

1.Histamine causes bronchoconstriction via H₁ receptors and this action is antagonized by adrenaline which causes bronchodilodation through 13₂ receptors (option d)

2.Leukotrienes cause bronchoconstriction via cystinyl leukotriene receptors and this action is antagonised by salhutamol which causes bronchodilatation through 13₂ receptors (option e)

Receptor antagonists (Pharmalogical antagonists)

• Receptor antagonists are those drugs that blocks the action of agonist by acting on same receptors. Example 1. Isoprenaline is 13₁ and p, receptor agonist while propranolol has antagonistic action on 13, and 0₂ receptors (option ‘c’)

about option a and b

o Adrenaline (a, + + R + + weak (3₃ agonist), isoprenaline (0, + 0₂ + 13, agonist) and salbutamol (13., agonist) —> all three are sympathomimetic drugs (not antagonists)

Ans. is ‘b’ i.e., β-carboline

Drugs acting at BZD site of GABA_A  receptors

o Agonist at BZD site of GABA_A receptor -4 Benzodiazepine, Zolpidem, Zopiclone, Zoleplon.

o Inverse agonist at BZD site of GABA_A receptor —> β-carboline

o Competitive antagonist at BZD site of GABA_A receptor —> Flumazenil

Ans. is ‘b’ i.e., Chemical

Protamine is an example of a chemical antagonist.

Ans. is `c’ i.e., Beta carboline

Ans. is ‘b’ i.e., Decreased affinity to receptors

Down regulation is a mechanism in which a hormone decrease the number or affinity of its receptors in target tissues.

Down-regulation may occur by decreasing the synthesis of new receptors, by increasing the degradation of existing receptors or by inactivating receptors.

The purpose of down-regulation is to reduce the sensitivity of the target tissue when hormone levels are high for an extended period of time.

Ans. is ‘d’ i.e., Affinity + Intrinsic activity –

Receptors are specific binding site with functional correlate.

In relation to action through receptors, two terms are important.

Ans. is ‘a’ i.e., Flumazenil

Flumazenil is a benzodiazepene analogue which competes with BZD agonists as well as inverse agonists for the BZD receptor and reverses their depressant or stimulant effects respectively.

It also antagonizes the action of Zolpidem, Zopiclone and Zopeplon as these drugs also act on BZD site.

Ans. is ‘a’ i.e., Antagonism

When one drug decreases or inhibits the action of other.

Effect of drugs A + B < effect of drug A + effect of drug B.

Antagonism may be :

a) Physical

Based on physical property

b) Chemical

The two drugs react chemically and form an inactive product.

c) Physiological/functional

The two drugs act on different receptors or by different mechanisms, but have opposite overt effects on the same physiological function ie have pharmacological effect in opposite direction.

(E) Receptor

The antagonist interferes with binding of the agonist with its receptor or inhibits the generation of response consequent to such binding.

Ans. is ‘b’ i.e., Binds to receptor and causes opposite action

Ans. is ‘a’ i.e., Physiological antagonism 

• Physiological antagonists are those that produce the opposite action by acting on different receptors. 

Antagonism

• When one drug decreases or inhibits the action of others.
• Effect of drugs A+ B < effect of drug A+ effect of drug B.
• Antagonism may be :

1. Physical
2. Based on physical property
3. Chemical
4. The two drugs react chemically and form an inactive product.
5. Physiological/functional
6. The two drugs act on different receptors or by different mechanisms but have opposite overt effects on the same physiological function ie have a pharmacological effect in opposite direction.
7. Receptor

• The antagonist interferes with binding of the agonist with its receptor or inhibits the generation of response consequent to such binding.