Inverse agonist
Encyclopedia
In the field of pharmacology
, 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 prerequisite for an inverse agonist response is that the receptor must have a constitutive (also known as intrinsic
or basal) level activity in the absence of any ligand
. An agonist increases the activity of a receptor above its basal level while an inverse agonist decreases the activity below the basal level. A neutral antagonist
has no activity in the absence of an agonist or inverse agonist but can block the activity of either.
The efficacy
of a full agonist is by definition 100%, a neutral antagonist, 0%, while an inverse agonist has < 0% (i.e., negative) efficacy.
s alprazolam
and diazepam
) elicit a sedative
effect while inverse agonists have anxiogenic
(for example, Ro15-4513
) or even convulsive effects (certain beta-carboline
s).
Two known endogenous inverse agonists are the agouti related peptide (AgRP
) and its associated peptide Agouti signaling peptide (ASIP) both are expressed in humans and each bind melanocortin receptors 4 and 1 (Mc4R
and Mc1R
) respectively with nanomolar affinities.
Pharmacology
Pharmacology is the branch of medicine and biology concerned with the study of drug action. More specifically, it is the study of the interactions that occur between a living organism and chemicals that affect normal or abnormal biochemical function...
, an inverse agonist is an agent that binds to the same receptor
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
as an agonist
Agonist
An agonist is a chemical that binds to a receptor of a cell and triggers a response by that cell. Agonists often mimic the action of a naturally occurring substance...
but induces a pharmacological response opposite to that agonist.
A prerequisite for an inverse agonist response is that the receptor must have a constitutive (also known as intrinsic
Intrinsic activity
Intrinsic activity or efficacy refers to the relative ability of a drug-receptor complex to produce a maximum functional response. This must be distinguished from the affinity, which is a measure of the ability of the drug to bind to its molecular target, and the EC50, which is a measure of the...
or basal) level activity in the absence of any ligand
Ligand
In coordination chemistry, a ligand is an ion or molecule that binds to a central metal atom to form a coordination complex. The bonding between metal and ligand generally involves formal donation of one or more of the ligand's electron pairs. The nature of metal-ligand bonding can range from...
. An agonist increases the activity of a receptor above its basal level while an inverse agonist decreases the activity below the basal level. A neutral antagonist
Receptor antagonist
A receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses...
has no activity in the absence of an agonist or inverse agonist but can block the activity of either.
The efficacy
Intrinsic activity
Intrinsic activity or efficacy refers to the relative ability of a drug-receptor complex to produce a maximum functional response. This must be distinguished from the affinity, which is a measure of the ability of the drug to bind to its molecular target, and the EC50, which is a measure of the...
of a full agonist is by definition 100%, a neutral antagonist, 0%, while an inverse agonist has < 0% (i.e., negative) efficacy.
Examples
An example of a receptor that possesses basal activity and for which inverse agonists have been identified is the GABAA receptor. Agonists for the GABAA receptor (such as the benzodiazepineBenzodiazepine
A benzodiazepine is a psychoactive drug whose core chemical structure is the fusion of a benzene ring and a diazepine ring...
s alprazolam
Alprazolam
Alprazolam is a short-acting anxiolytic of the benzodiazepine class of psychoactive drugs. Alprazolam, like other benzodiazepines, binds to specific sites on the GABAA gamma-amino-butyric acid receptor...
and diazepam
Diazepam
Diazepam , first marketed as Valium by Hoffmann-La Roche is a benzodiazepine drug. Diazepam is also marketed in Australia as Antenex. It is commonly used for treating anxiety, insomnia, seizures including status epilepticus, muscle spasms , restless legs syndrome, alcohol withdrawal,...
) elicit a sedative
Sedative
A sedative or tranquilizer is a substance that induces sedation by reducing irritability or excitement....
effect while inverse agonists have anxiogenic
Anxiogenic
An anxiogenic substance is one that causes anxiety. Anxiogenic effects can be measured by, for example, the hole-board test in rats and mice. A number of agents are used to provoke anxiety or panic in experimental models...
(for example, Ro15-4513
Ro15-4513
Ro15-4513 is a weak partial inverse agonist of the benzodiazepine class of drugs, developed by Hoffmann–La Roche in 1984, and is structurally related to the benzodiazepine antidote flumazenil.-Original development as alcohol antidote:...
) or even convulsive effects (certain beta-carboline
Beta-carboline
β-Carboline is an organic amine that is the prototype of a class of compounds known as β-carbolines.-Pharmacology:...
s).
Two known endogenous inverse agonists are the agouti related peptide (AgRP
Agouti-related peptide
Agouti-related protein also called Agouti-related peptide is a neuropeptide produced in the brain by the AgRP/NPY neuron. It is only synthesised in NPY containing cell bodies located in the ventromedial part of the arcuate nucleus in the hypothalamus...
) and its associated peptide Agouti signaling peptide (ASIP) both are expressed in humans and each bind melanocortin receptors 4 and 1 (Mc4R
Melanocortin 4 receptor
Melanocortin receptor 4 is a protein that in humans is encoded by the MC4R gene. It encodes the MC4 protein, a G-protein coupled receptor that binds α-melanocyte stimulating hormone...
and Mc1R
Melanocortin 1 receptor
The melanocortin 1 receptor , also known as melanocyte-stimulating hormone receptor , melanin-activating peptide receptor, or melanotropin receptor, is a G protein-coupled receptor which binds to a class of pituitary peptide hormones known as the melanocortins, of which include adrenocorticotropic...
) respectively with nanomolar affinities.