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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;<ref>Template:Cite journal</ref> 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.<ref name="pmid27955830">Template:Cite journal</ref>
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.<ref>Template:Cite journal</ref> 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.
ExamplesEdit
Receptors for which inverse agonists have been identified include the GABAA, 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 agonistsEdit
An example of a receptor site that possesses basal activity and for which inverse agonists have been identified is the GABAA receptors. Agonists for GABAA 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).<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>
G protein-coupled receptor inverse agonistsEdit
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.<ref name="pmid9450927">Template:Cite journal</ref>
The opioid antagonists naloxone and naltrexone act as neutral antagonists of 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.<ref name="pmid11413242">Template:Cite journal</ref>
Nearly all antihistamines acting at H1 receptors and H2 receptors have been shown to be inverse agonists.<ref name=":0">Template:Cite journal</ref>
The beta blockers carvedilol and bucindolol have been shown to be low level inverse agonists at beta adrenoceptors.<ref name=":0" />
Mechanisms of actionEdit
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.<ref name=":2">Template:Cite journal</ref> Because of this, they exhibit a spectrum of activity below the Intrinsic activity level.<ref name=":2" /><ref name=":1">Template:Cite journal</ref> Changes in constitutive activity of receptors affect response levels from ligands like inverse agonists.<ref>Template:Cite journal</ref>
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.<ref name=":02">Template:Cite journal</ref> Under this model, current thinking is that the GPCRs can exist in a continuum of active and inactive states when no ligand is present.<ref name=":02" /> Inverse agonists stabilize the inactive states, thereby suppressing agonist-independent activity.<ref name=":02" /> However, the implementation of 'constitutively active mutants'<ref name=":02" /> of GPCRs change their intrinsic activity.<ref name=":2" /><ref name=":1" /> 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 alsoEdit
ReferencesEdit
External linksEdit
- {{#invoke:citation/CS1|citation
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- Inverse Agonists: An Illustrated Tutorial Panesar K, Guzman F. Pharmacology Corner. 2012