Inpharmacology, aninverse agonist is adrug that binds to the samereceptor as anagonist but induces a pharmacological response opposite to that of the agonist.
Aneutral antagonist has no activity in the absence of an agonist or inverse agonist but can block the activity of either;[1] they are in fact sometimes calledblockers (examples includealpha blockers,beta blockers, andcalcium channel blockers). 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 aconstitutive (also known asintrinsic or basal) level of activity in the absence of anyligand.[3] An agonist increases the activity of a receptor above its basal level, whereas an inverse agonist decreases the activity below the basal level.
Theefficacy 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 for which inverse agonists have been identified include theGABAA,melanocortin,mu opioid,histamine andbeta adrenergic receptors. Bothendogenous andexogenous inverse agonists have been identified, as have drugs at ligand gated ion channels and at G protein-coupled receptors.
An example of a receptor site that possesses basal activity and for which inverse agonists have been identified is theGABAA receptors. Agonists for GABAA receptors (such asmuscimol) create arelaxant effect, whereas inverse agonists haveagitation effects (for example,Ro15-4513) or evenconvulsive andanxiogenic effects (certainbeta-carbolines).[4][5]
Two known endogenous inverse agonists are theAgouti-related peptide (AgRP) and its associated peptideAgouti signalling peptide (ASIP). AgRP and ASIP appear naturally in humans and bindmelanocortin receptors 4 and 1 (Mc4R andMc1R), respectively, with nanomolar affinities.[6]
Theopioid antagonistsnaloxone andnaltrexone act asneutral antagonists of themu opioid receptors under basal conditions, but as inverse agonists when an opioid such asmorphine is bound to the same channel. 6α-naltrexo,6β-naltrexol, 6β-naloxol, and 6β-naltrexamine actedneutral antagonists regardless of opioid binding and caused significantly reduced withdrawal jumping when compared tonaloxone andnaltrexone.[7]
Nearly all antihistamines acting atH1 receptors andH2 receptors have been shown to be inverse agonists.[8]
Thebeta blockerscarvedilol andbucindolol have been shown to be low level inverse agonists atbeta adrenoceptors.[8]
Likeagonists, 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 ofreceptor, mutants of receptors, binding affinities and whether the effects are exerted acutely or chronically based on receptor population density.[9] Because of this, they exhibit a spectrum of activity below theIntrinsic activity level.[9][10] Changes in constitutive activity of receptors affect response levels from ligands like inverse agonists.[11]
To illustrate, mechanistic models have been made for how inverse agonists induce their responses onG protein-coupled receptors (GPCRs). Many types of Inverse agonists forGPCRs have been shown to exhibit the following conventionally accepted mechanism.
Based on the ExtendedTernary complex model, the mechanism contends that inverse agonists switch the receptor from an active state to an inactive state by undergoing conformational changes.[12] Under this model, current thinking is that theGPCRs can exist in a continuum of active and inactive states when no ligand is present.[12] Inverse agonists stabilize the inactive states, thereby suppressing agonist-independent activity.[12] However, the implementation of 'constitutively active mutants'[12] ofGPCRs change their intrinsic activity.[9][10] 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).