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 A receptor antagonist is a type of receptor ligand or drug that blocks or dampens a biological response by binding to and blocking a receptor rather than activating it like an agonist. Antagonist drugs interfere in the natural operation of recep ...

has no activity in the absence of an agonist or inverse agonist but can block the activity of either. Inverse agonists have opposite actions to those of agonists but the effects of both of these can be blocked by antagonists. A prerequisite for an inverse agonist response is that the receptor must have a constitutive (also known as

intrinsic In science and engineering, an intrinsic property is a property of a specified subject that exists itself or within the subject. An extrinsic property is not essential or inherent to the subject that is being characterized. For example, mass ...

or basal) level of activity in the absence of any

ligand In coordination chemistry, a ligand is an ion or molecule ( functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's elec ...

. 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 GABA_A,

melanocortin The melanocortins are a family of neuropeptide hormones which are the ligands of the melanocortin receptorsEricson, M.D., et al., ''Bench-top to clinical therapies: A review of melanocortin ligands from 1954 to 2016.'' Biochim Biophys Acta Mol Basi ...

, mu opioid,

histamine Histamine is an organic nitrogenous compound involved in local immune responses, as well as regulating physiological functions in the gut and acting as a neurotransmitter for the brain, spinal cord, and uterus. Since histamine was discovered ...

and

beta adrenergic receptor The adrenergic receptors or adrenoceptors are a class of G protein-coupled receptors that are targets of many catecholamines like norepinephrine (noradrenaline) and epinephrine (adrenaline) produced by the body, but also many medications like beta ...

s. Both endogenous and

exogenous In a variety of contexts, exogeny or exogeneity () is the fact of an action or object originating externally. It contrasts with endogeneity or endogeny, the fact of being influenced within a system. Economics In an economic model, an exogeno ...

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 GABA_A receptors. Agonists for GABA_A receptors (such as

muscimol Muscimol (also known as agarin or pantherine) is one of the principal psychoactive constituents of '' Amanita muscaria'' and related species of mushroom. Muscimol is a potent and selective orthosteric agonist for the GABAA receptors and displa ...

) create a relaxant effect, whereas inverse agonists have agitation effects (for example, Ro15-4513) or even

convulsive A convulsion is a medical condition where the body muscles contract and relax rapidly and repeatedly, resulting in uncontrolled shaking. Because epileptic seizures typically include convulsions, the term ''convulsion'' is sometimes used as a s ...

and anxiogenic effects (certain

beta-carboline β-Carboline (9''H''- pyrido ,4-''b'' ndole) represents the basic chemical structure for more than one hundred alkaloids and synthetic compounds. The effects of these substances depend on their respective substituent. Natural β-carbolines prima ...

s).

G protein-coupled receptor inverse agonists

Two known endogenous inverse agonists are the

Agouti-related peptide Agouti-related protein (AgRP), also called agouti-related peptide, is a neuropeptide produced in the brain by the AgRP/NPY neuron. It is synthesized in neuropeptide Y (NPY)-containing cell bodies located in the ventromedial part of the arcuate nu ...

(AgRP) and its associated peptide

Agouti signalling peptide Agouti-signaling protein is a protein that in humans is encoded by the ASIP gene. It is responsible for the distribution of melanin pigment in mammals. Agouti interacts with the melanocortin 1 receptor to determine whether the melanocyte (pigment ...

(ASIP). AgRP and ASIP appear naturally in humans and bind

melanocortin receptors Melanocortin receptors are members of the rhodopsin family of 7-transmembrane G protein-coupled receptors. There are five known members of the melanocortin receptor system each with differing specificities for melanocortins: * . MC1R is associa ...

4 and 1 ( Mc4R and

Mc1R The melanocortin 1 receptor (MC1R), also known as melanocyte-stimulating hormone receptor (MSHR), melanin-activating peptide receptor, or melanotropin receptor, is a G protein–coupled receptor that binds to a class of pituitary peptide hormones ...

), respectively, with nanomolar affinities. The

opioid antagonist An opioid antagonist, or opioid receptor antagonist, is a receptor antagonist that acts on one or more of the opioid receptors. Naloxone and naltrexone are commonly used opioid antagonist drugs which are competitive antagonists that bind to the ...

naloxone Naloxone, sold under the brand names Narcan (4 mg) and Kloxxado (8 mg) among others, is a medication used to reverse or reduce the effects of opioids. It is commonly used to counter decreased breathing in opioid overdose. Effects begin withi ...

and

naltrexone Naltrexone, sold under the brand name Revia among others, is a medication primarily used to manage alcohol or opioid use disorder by reducing cravings and feelings of euphoria associated with substance use disorder. It has also been foun ...

act as neutral antagonists of the mu opioid receptors under basal conditions, but as inverse agonists when an opioid such as

morphine Morphine is a strong opiate that is found naturally in opium, a dark brown resin in poppies (''Papaver somniferum''). It is mainly used as a pain medication, and is also commonly used recreationally, or to make other illicit opioids. T ...

as bound to the same channel. 6α-naltrexo,

6β-naltrexol 6β-Naltrexol, or 6β-hydroxynaltrexone (developmental code name AIKO-150), is a peripherally-selective opioid receptor antagonist related to naltrexone. It is a major active metabolite of naltrexone formed by hepatic dihydrodiol dehydrogenase ...

, 6β-naloxol, and 6β-naltrexamine acted neutral antagonists regardless of opioid binding and caused significantly reduced withdrawal jumping when compared to

and

. Nearly all antihistamines acting at H1 receptors and H2 receptors have been shown to be inverse agonists. The

beta blockers Beta blockers, also spelled β-blockers, are a class of medications that are predominantly used to manage abnormal heart rhythms, and to protect the heart from a second heart attack after a first heart attack ( secondary prevention). They are ...

carvedilol and bucindolol have been shown to be low level inverse agonists at beta adrenoceptors.

Mechanisms of Action

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. Because of this, they exhibit a spectrum of activity below the

Intrinsic activity Intrinsic activity (IA) and efficacy refer 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 mol ...

level. Changes in constitutive activity of receptors affect response levels from ligands like inverse agonists. To illustrate, mechanistic models have been made for how inverse agonists induce their responses on

G protein-coupled receptor G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily-related p ...

s (GPCRs). Many types of Inverse agonists for GPCRs have been shown to exhibit the following conventionally accepted mechanism. Based on the Extended

Ternary complex A ternary complex is a protein complex containing three different molecules that are bound together. In structural biology, ''ternary complex'' can also be used to describe a crystal containing a protein with two small molecules bound, for example ...

model, the mechanism contends that inverse agonists switch the receptor from an active state to an inactive state by undergoing conformational changes. Under this model, current thinking is that the GPCRs can exist in a continuum of active and inactive states when no ligand is present. Inverse agonists stabilize the inactive states, thereby suppressing agonist-independent activity. However, the implementation of 'constitutively active mutants' of GPCRs change their intrinsic activity. 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).

References

External links