Inverse agonist

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] 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 GABA_A, melanocortin, mu opioid, histamine and 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 GABA_A receptors. Agonists for GABA_A receptors (such as muscimol) create a relaxant effect, whereas inverse agonists have agitation effects (for example, Ro15-4513) or even convulsive and anxiogenic effects (certain beta-carbolines).^[4][5]

G protein-coupled receptor inverse agonists[]

Two known endogenous inverse agonists are the Agouti-related peptide (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), respectively, with nanomolar affinities.^[6]

The opioid antagonists naloxone and naltrexone are also partial inverse agonists at mu opioid receptors.^{[citation needed]}

Nearly all antihistamines acting at H1 receptors and H2 receptors have been shown to be inverse agonists.^[7]

The beta blockers carvedilol and bucindolol have been shown to be low level inverse agonists at beta adrenoceptors.^[7]

See also[]

• Agonist
• Receptor antagonist

References[]

External links[]

• Jeffries WB (1999-02-17). "Inverse Agonists for Medical Students". Office of Medical Education - Courses - IDC 105 Principles of Pharmacology. Creighton University School of Medicine - Department of Pharmacology. Retrieved 2008-08-12.
• Inverse Agonists: An Illustrated Tutorial Panesar K, Guzman F. Pharmacology Corner. 2012