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 or basal) level of activity in the absence of any ligand. 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.
Receptors which inverse agonists have been identified for 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.
Drugs at ligand gated ion channelsEdit
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).
Drugs at G protein-coupled receptorsEdit
Two known endogenous inverse agonists are the Agouti-related peptide (AgRP) and its associated peptide Agouti signalling peptide (ASIP). Both appear naturally in humans, and each binds melanocortin receptors 4 and 1 (Mc4R and Mc1R), respectively, with nanomolar affinities.
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