Editing Inverse agonist (section)

== Mechanisms of action ==
[[File:Basal_activity_of_receptor_changes.png|thumb|431x431px|Figure 2: Example of changes in Intrinsic activity based on mutations and the presence of inverse agonists. (assuming the inverse agonist has the same binding affinity for both the normal and mutated receptor)]]
Like [[Agonist|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 (biochemistry)|receptor]], mutants of receptors, binding affinities and whether the effects are exerted acutely or chronically based on receptor population density.<ref name=":2">{{Cite journal |last=Prather |first=Paul L. |date=2004-01-05 |title=Inverse agonists: tools to reveal ligand-specific conformations of G protein-coupled receptors |url=https://pubmed.ncbi.nlm.nih.gov/14722344/ |journal=Science's STKE: Signal Transduction Knowledge Environment |volume=2004 |issue=215 |pages=pe1 |doi=10.1126/stke.2152004pe1 |issn=1525-8882 |pmid=14722344|s2cid=22336235 }}</ref> Because of this, they exhibit a spectrum of activity below the [[Intrinsic activity]] level.<ref name=":2" /><ref name=":1">{{Cite journal |last1=Hirayama |first1=Shigeto |last2=Fujii |first2=Hideaki |date=2020 |title=δ Opioid Receptor Inverse Agonists and their In Vivo Pharmacological Effects |url=https://pubmed.ncbi.nlm.nih.gov/32238139/ |journal=Current Topics in Medicinal Chemistry |volume=20 |issue=31 |pages=2889–2902 |doi=10.2174/1568026620666200402115654 |issn=1873-4294 |pmid=32238139|s2cid=214767114 }}</ref> Changes in constitutive activity of receptors affect response levels from ligands like inverse agonists.<ref>{{Cite journal |last1=Berg |first1=Kelly A. |last2=Clarke |first2=William P. |date=2018-10-01 |title=Making Sense of Pharmacology: Inverse Agonism and Functional Selectivity |journal=The International Journal of Neuropsychopharmacology |volume=21 |issue=10 |pages=962–977 |doi=10.1093/ijnp/pyy071 |issn=1469-5111 |pmc=6165953 |pmid=30085126}}</ref>

To illustrate, mechanistic models have been made for how inverse agonists induce their responses on [[G protein-coupled receptor]]s (GPCRs). Many types of Inverse agonists for [[G protein-coupled receptor|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">{{Cite journal |last=Strange |first=Philip G. |date=February 2002 |title=Mechanisms of inverse agonism at G-protein-coupled receptors |url=https://pubmed.ncbi.nlm.nih.gov/11830266/ |journal=Trends in Pharmacological Sciences |volume=23 |issue=2 |pages=89–95 |doi=10.1016/s0165-6147(02)01993-4 |issn=0165-6147 |pmid=11830266}}</ref> Under this model, current thinking is that the [[G protein-coupled receptor|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 [[G protein-coupled receptor|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).