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inverse agonist???

Matt Jones jonesmat at ohsu.edu
Thu Oct 1 12:35:18 EST 1998

In article <361318B0.92570156 at scripps.edu> Michael Bracey,
bracey at scripps.edu writes:
>OK, I found this.  Does this suffice?
>Antagonists only exert their actions in the presence of agonists,
>but have no activity of their own in the absence of agonists. Still
>other drugs do the opposite of agonists, and are calles inverse
>agonists. Thus,
>drugs acting at a receptor exist in a spectrum from full agonist to
>antagonist to inverse agonist.

Hi  Michael,

The relationship of agonist-antagonist-partial agonist-inverse agonist is
a complex one, and in my opinion the distinctions between these things
are a bit cloudy and partly a holdover from historical views of
drug-receptor interactions. But you seem to basically already have the
idea judging from your last two posts. Let me see if I can clarify a
little bit, using the example of GABA-A receptors.

GABA-A receptors are ligand-gated channels that open when they bind GABA.
So GABA is the endogenous "agonist" of the receptor.  Traditionally,
drugs like bicuculline are considered to be "antagonists" because they
block the ability of the agonist to activate the channel. Part of the
classical definition of antagonist requires that the drug doesn't do
anything by itself when the agonist isn't around. But this introduces a
problem. If there's no GABA around, then the _channel_ isn't doing
anything, and so when you put on an "antagonist" you don't see any effect
(you can't block a zero response). And that's exactly what happens when
you put bicuculline on in the absence of GABA. But note that this only
tells you that bicuculline isn't an agonist, it doesn't tell you whether
it's an antagonist or an inverse agonist. 

Now, it turns out that there _are_ ways of getting GABA channels to open
in the absence of GABA. Applying many general anesthetics, for example,
directly gate the channel by binding to a site distinct from that for
GABA. If you apply an anesthetic in the absence of GABA (pentobarbitone,
for example) you activate a current, and surprisingly this current can be
blocked by bicuculline, which was previously thought to be an
"antagonist". But here we see bicuculline having an effect in the absence
of GABA, so it should really be thought of as an "inverse agonist",
because it is doing the opposite of what GABA would be doing. A nice
paper about this was published in J. Neurosci. by Ueno et al. within the
last year or two.

The classical distinction runs something like this:

If it causes a response, it's an agonist.
If it causes a response, at a saturating dose, that is smaller than the
response to another agonist, it's a "partial agonist".
If it inhibits the response caused by an agonist, it's an antagonist.
If there is some baseline level of activity *in the absence of agonist*,
and the drug inhibits that, it's an inverse agonist.

Note the importance of the "baseline" criteria for defining an inverse

But a more accurate and mechanistic description will view all the ligands
that bind at a certain site as "allosteric modulators", meaning that they
all bind and do _something_. Some might be "positive allosteric
modulators" like agonists and partial agonists. Some might be "negative
allosteric modulators" like inverse agonists. It is no longer entirely
clear whether there is such a thing as a pure antagonist, technically
speaking.  But for practical experimental purposes, the original
distinctions are still quite useful. 

Other examples of agonist-inverse antagonist systems are the
benzodiazepine site on the GABA-A receptor, the dihydropyridine site on
voltage-gated calcium channels, and lots of G-protein systems, including
some opiod receptors (c.f., papers by Tim Hales and colleagues).


Matt Jones

Mathew V. Jones
The Vollum Institute
3181 S.W. Sam Jackson Park Rd.
Portland, OR   97201

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