Talk:Inverse agonist

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R015-4513[edit]

The description does not seem to fit the profile of a reverse agonist. Rather, this seems to fit the description of an antagonist. R015-4513 appears to simply block access to the GABA channel preventing the access of alcohol. Since it elicits no action from the receptor change, this does not fit the definition of a reverse agonist. —Preceding unsigned comment added by 141.150.53.30 (talk) 18:20, 30 October 2007 (UTC)

R015-4513 definitely acts as an inverse agonist on the GABAA receptor causing a decrease in chloride conductance through this channel relative to the conductance in the absence of any ligand. Alcohol has the opposite effect (i.e., an increase in chloride current). It is not known where alcohol binds on the GABAA receptor but it does appear to bind on a site that differs from the benzodiazepine binding site. Boghog (talk) 04:57, 22 September 2011 (UTC)

We need a Pluto Talk[edit]

Agonists, inverse agonists, antagonists, functional selectivity. There are too many variations in individual definitions of all of these. I often hear inverse agonists being described as antagonists by knowledgable people in pharmacology, because when they were educated, there was nothing other than the on / off dogma associated with the terms. The problem in clarification extends too to binding sites of receptors. There should be a difference in name between agonists which work at the same binding site of a receptor and those which do not. I hereby motion that we raise this issue, whether it be here on wikipedia or in a conference to discuss this issue so that the confusion does not continue into the future.--Carlwfbird 05:15, 26 September 2006 (UTC)

WAIT!
something that is being left out here is that the receptor binding site is on an inactive receptor. yes it is the same receptor, but in a different conformation. using the lock and key analogy, an inverse agonist binds the lock before it is inserted in the door. a true agonist binds the lock when it is in the door and acting as a lock. in the cell, the lock is constantly changing location from in the door and out of the door.-- JW 27 September 2007
Fine. But still, there is not much consensus on this. Publications can be found describing this mechanism as antagonism. This is a very good molecular definition. Physiologists and animal behavior studies still use inverse agonism in yet a different definition - a ligand which elicits the opposite effect of a known agonist. —Preceding unsigned comment added by 71.127.212.33 (talk) 03:18, 16 January 2008 (UTC)
The issue of where various ligands bind (orthosteric – same site or allosteric – different sites) is quite distinct from the activity that they invoke (agonism vs. antagonism vs inverse agonism). It is possible to have both orthosteric agonists and inverse agonists as well as allosteric agonists and inverse agonists. The functional activity that a ligand invokes, be it agonism or inverse agonism, is a result of a conformational change in the receptor protein. Change the conformation one way, activity is increased (agonism), and change it a second way, the activity is decreased (inverse agonism). Stabilize the native conformation that exists in the absence of any ligand, there is no change in activity (antagonism), except that antagonists can block the binding of either agonists or inverse agonists. Boghog (talk) 06:36, 22 September 2011 (UTC)

Okay[edit]

The bulk of the article says that the biological activity of an inverse agonist is the opposite of that of an agonist, and the accompanying graphic suggests the same. But the definition in the lead says that the inverse agonist stops the constitutive activity of the receptor, and the article to which "constitutive activity" links defines it as the activity of the receptor when it is empty. Am I missing something? 69.140.152.55 (talk) 15:53, 11 July 2008 (UTC)

Agonists, antagonists and inverse agonists were all terms which were introduced to explain the responses of a receptor once a ligand binds. receptors that are on (show activity) when no ligand is bound to the receptor are refered to as constitutively active. This may happen when a mutation occurs in the sequence of the gene the mutated gene now makes the receptor that is always on. Where receptors are always on, empty as you refer to them and when the ligand binds it turns them off which refer to as an inverse agonist. Other ligands can increase the activity of a receptor or in other cases where a receptor showing no activity (receptor in the off state) turn it on (agonists). ligands which bind to receptors and produce no change in activity in the receptor but block anything else binding (agonist, partial agonist, inverse agonist) are called antagonists. Example of always on receptors include: mutations in the thyroid-stimulating hormone receptors which results in Hyperthyroidism. Hope this helps you visualise that a receptor that is always on can occur and the picture in the article shows a receptor showing what happens when a receptor is on and a inverse agonist binds which will turn it off Lilypink (talk) —Preceding comment was added at 11:33, 15 July 2008 (UTC)
I still have a problem with the picture and "constitutive activity." If a receptor is constitutively active, how is the baseline 0? From what I understand, we should start with a baseline of >0. The limit of full agonist is still 1, the partial agonist is between 1 and 0, the antagonist is the baseline, and the limit of an inverse agonist would be 0. Please correct me if I'm wrong. 71.197.154.212 (talk) 03:58, 22 September 2011 (UTC)
What matters is the relative, not absolute numbers on the Y-axis of the figure. The constitutive level of activity is often by definition set to zero so that reduction of activity below basal is negative and increases above basal are positive. In many cases, agonists for a particular receptor were discovered before inverse agonists. Hence the full range of activity appeared to span from zero (when no ligand or an antagonist is bound) to one hundred (when a full agonist is bound). Later, when an inverse agonist was discovered, it was easiest to retain the existing activity scale and designate activity below basal as negative. As you point out, one could also set the bottom of the scale to zero. These two alternative activity scales are completely analogous to the Celsius (lowest value set to -273°) and Kelvin (lowest value set to 0°) temperature scales and are equally valid. Boghog (talk) 04:57, 22 September 2011 (UTC)
Very well explained Lilypink and Boghog. I find nothing wrong with your explanation and feel you picked the best examples possible to demonstrate this concept to a layman. Well done and thank you! — Preceding unsigned comment added by 173.206.28.194 (talk) 18:56, 17 August 2013 (UTC)

Merge with agonists page?[edit]

I wonder if the contents of the inverse agonist article could infact be inserted into the "agonists" article, as other types of agonist, e.g. partial agonist do not have their own article. —Preceding unsigned comment added by Werlop (talkcontribs) 17:56, 1 May 2008 (UTC)

Oppose – A partial agonist has the same type of activity as a full agonist, just not as pronounced. An inverse agonist has an activity that is opposite an agonist. Hence partial and full agonists are qualitatively the same whereas agonist and inverse agonists are quite distinct. Hence it is fully justified to have separate articles on agonists and inverse agonists. Boghog (talk) 04:57, 22 September 2011 (UTC)
I feel the three major characteristics should have their own pages (agonist, antagonist and inverse agonist) with the subtypes falling within their respective divisions (full and partial agonists in agonist page etc.)Wesdaco (talk) 19:04, 17 August 2013 (UTC)

Differentiate from antagonist[edit]

Article does not seem to explain how antagonists are different from inverse agonists - Could anyone add a one-liner to the intro ? - Rod57 (talk) 12:16, 17 April 2016 (UTC)

The last line in the second paragraph states: A neutral antagonist has no activity in the absence of an agonist or inverse agonist but can block the activity of either. Doesn't this cover it? To make the distinction clearer, I have moved this sentence from the second to the first paragraph in this edit. Is this any better? Boghog (talk) 16:30, 17 April 2016 (UTC)