pharmacology Pharmacology is a branch of medicine, biology and pharmaceutical sciences concerned with drug or medication action, where a drug may be defined as any artificial, natural, or endogenous (from within the body) molecule which exerts a biochemi ...

, an inverse agonist is a

drug A drug is any chemical substance that causes a change in an organism's physiology or psychology when consumed. Drugs are typically distinguished from food and substances that provide nutritional support. Consumption of drugs can be via inhal ...

that binds to the same receptor as an

agonist An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...

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. 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 ele ...

. 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, 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 in ...

and beta adrenergic receptors. Both

endogenous Endogenous substances and processes are those that originate from within a living system such as an organism, tissue, or cell. In contrast, exogenous substances and processes are those that originate from outside of an organism. For example, ...

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 GABA_A receptors. Agonists for GABA_A receptors (such as muscimol) create a

relaxant A muscle relaxant is a drug that affects skeletal muscle function and decreases the muscle tone. It may be used to alleviate symptoms such as muscle spasms, pain, and hyperreflexia. The term "muscle relaxant" is used to refer to two major therap ...

effect, whereas inverse agonists have agitation effects (for example, Ro15-4513) or even convulsive and anxiogenic effects (certain beta-carbolines).

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 n ...

(AgRP) and its associated peptide Agouti signalling peptide (ASIP). AgRP and ASIP appear naturally in humans and bind melanocortin receptors 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 hormon ...

), 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 found to ...

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. Ther ...

as 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

and

. Nearly all antihistamines acting at H1 receptors and

H2 receptors H2 receptors are positively coupled to adenylate cyclase via Gs. It is a potent stimulant of cAMP production, which leads to activation of protein kinase A. PKA functions to phosphorylate certain proteins, affecting their activity. The drug beta ...

have been shown to be inverse agonists. The beta blockers carvedilol and

bucindolol Bucindolol is a non-selective beta blocker with additional weak alpha-blocking properties and some intrinsic sympathomimetic activity. It was under review by the FDA in the United States for the treatment of heart failure in 2009, but was reject ...

have been shown to be low level inverse agonists at

beta adrenoceptors 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 ...

Mechanisms of Action

Agonist An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...

s, 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 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 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