Inverse agonist

Source: Wikipedia, the free encyclopedia.
Not to be confused with Antagonist or Protagonist.
Dose response curves of a full agonist, partial agonist, neutral antagonist, and inverse agonist

In pharmacology, an inverse agonist is a drug that binds to the same receptor as an agonist but induces a pharmacological response opposite to that of the agonist.

A neutral antagonist has no activity in the absence of an agonist or inverse agonist but can block the activity of either;[1] they are in fact sometimes called blockers (examples include alpha blockers, beta blockers, and calcium channel blockers). Inverse agonists have opposite actions to those of agonists but the effects of both of these can be blocked by antagonists.[2]

A prerequisite for an inverse agonist response is that the receptor must have a constitutive (also known as intrinsic or basal) level of activity in the absence of any ligand.[3] An agonist increases the activity of a receptor above its basal level, whereas an inverse agonist decreases the activity below the basal level.

The efficacy of a full agonist is by definition 100%, a neutral antagonist has 0% efficacy, and an inverse agonist has < 0% (i.e., negative) efficacy.

Examples

Receptors for which inverse agonists have been identified include the

beta adrenergic receptors. Both endogenous and exogenous
inverse agonists have been identified, as have drugs at ligand gated ion channels and at G protein-coupled receptors.

Ligand gated ion channel inverse agonists

An example of a receptor site that possesses basal activity and for which inverse agonists have been identified is the

beta-carbolines).[4][5]

G protein-coupled receptor inverse agonists

Two known endogenous inverse agonists are the

melanocortin receptors 4 and 1 (Mc4R and Mc1R), respectively, with nanomolar affinities.[6]

The

mu opioid receptors under basal conditions, but as inverse agonists when an opioid such as morphine is bound to the same channel. 6α-naltrexo, 6β-naltrexol, 6β-naloxol, and 6β-naltrexamine acted neutral antagonists regardless of opioid binding and caused significantly reduced withdrawal jumping when compared to naloxone and naltrexone.[7]

Nearly all antihistamines acting at

H2 receptors have been shown to be inverse agonists.[8]

The

beta adrenoceptors.[8]

Mechanisms of action

Figure 2: Example of changes in Intrinsic activity based on mutations and the presence of inverse agonists. (assuming the inverse agonist has the same binding affinity for both the normal and mutated receptor)

Like agonists, inverse agonists have their own unique ways of inducing pharmacological and physiological responses depending on many factors, such as the type of inverse agonist, the type of receptor, mutants of receptors, binding affinities and whether the effects are exerted acutely or chronically based on receptor population density.[9] Because of this, they exhibit a spectrum of activity below the Intrinsic activity level.[9][10] Changes in constitutive activity of receptors affect response levels from ligands like inverse agonists.[11]

To illustrate, mechanistic models have been made for how inverse agonists induce their responses on G protein-coupled receptors (GPCRs). Many types of Inverse agonists for GPCRs have been shown to exhibit the following conventionally accepted mechanism.

Based on the Extended Ternary complex model, the mechanism contends that inverse agonists switch the receptor from an active state to an inactive state by undergoing conformational changes.[12] Under this model, current thinking is that the GPCRs can exist in a continuum of active and inactive states when no ligand is present.[12] Inverse agonists stabilize the inactive states, thereby suppressing agonist-independent activity.[12] However, the implementation of 'constitutively active mutants'[12] of GPCRs change their intrinsic activity.[9][10] Thus, the effect an inverse agonist has on a receptor depends on the basal activity of the receptor, assuming the inverse agonist has the same binding affinity (as shown in the figure 2).

See also

References

  1. PMID 15063082
    .
  2. S2CID 25113284
    .
  3. PMID 30085126
    .
  4. PMID 2457076. Archived
    from the original on 2021-05-31. Retrieved 2008-04-21.
  5. PMID 8148363
    .
  6. PMID 9450927
    .
  7. S2CID 10026688
    .
  8. ^
    PMID 22021988
    .
  9. ^
    S2CID 22336235
    .
  10. ^
    S2CID 214767114
    .
  11. PMID 30085126
    .
  12. ^
    PMID 11830266
    .

External links
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