The way I read this, the ratio of DA release to DA reuptake inhibition can be selectively controlled (don't think it can be increased, but DAT-mediated release can always be slowed down).
The antagonist just reverts the ratio to normal, or so I think...
My verdict: these compounds are strange as hell. I've not really seen anything like this before.
The
first table I linked in my former post claims it only as "antagonist-like", and I believe that's only in comparison to the 'agonist-like' moniker given to the other three compounds. I assume given to them under the pretense of their initially doing whatever novel effect was broadly meant to be ascribed to them.
Yet the "antagonist" has "no effect" on
amphetamine induced DAT-mediated DA release (whereas the 'agonists' do, by impeding it. Much as you noted sekio; a slowing of release as by partial inhibition). Interestingly, on this same table and row (under that same heading of
...induced...release), cocaine is rather a "competitive inhibitor" (for amphetamine binding and activity on DAT), meaning it cannot bind whatsoever if amphetamine has induced 'DAT mediated DA release', but, alternately, amphetamine cannot mediate release by altering DAT if and while cocaine is bound. This much I knew, and I hope I am not reading my previous knowledge wrongly into it.
Furthermore, this "antagonist" has
partial inhibitor functionality upon
DA Uptake i.e. the reuptake mechanism of DAT (unless I wrongly am projecting my own notions & preconceptions here too as I may be there). On that same uptake category of the table, cocaine is again described as a "
“Normal” competitive inhibitor" (here I assume that title is again used to assign to cocaine such an allusion generally. Though here under this column of the table in question it is in reference to another specific quality: that of being an inhibitor to DA binding with the uptake pump portion of DAT; a reuptake inhibitor of DA or DRI).
(I am ignorant however as to what the
efflux of [3H]MPP+ segment of the table refers to, or what role that plays in DAT. I presume the columns referring to RTI-55 mean another ligand that has an allosteric binding site. So it's the first and final column from where I am extrapolating the entirety of my simple analysis. The
B/V max footnotes are more terms to which I am ignorant. I assume regardless that they are in the company of other similar variables which are too invested in maths for me, or maybe anyone, to derive a particular set of entailing data from. Anyone please enlighten me if you're able.)
This makes the 'antagonist' more interesting to me as a potential recreational adjunct to releasing agents. Via their imparting some measure of re-uptake inhibition overlap at which transporters are affected by DRAs without that mutual exclusion usual between DRIs and releasing agents.
The 'agonists' seemingly only moderate amphetamines effects 'allosterically' straight across the board, which includes also the slower release of DA. Whereas the "antagonist-like" one doesn't, and is, I assume, only antagonistic in regard to this class of dopaminergics themselves by their doing the same otherwise, but without effecting release rate. i.e. while competitively (against the agonists) allowing the efflux which the agonists do not...
(...counter-intuitively conveying what one would imagine the name "antagonist", when used in contrast with "agonist", to imply. At least when for something as straight across as their meaning when for *receptor* ligands; having as they do directly functional relationships with action potentials. It seems that with *transporters* those two labels are not as straight forward and are more literally relative. My hunch for that reasoning is confirmed only by their own wording in what they publish and my own sparse knowledge at how ligands are thus described in papers otherwise: e.g. cocaine-antagonists being defined by having cocaine's binding site occupied, so remaining unaffected, while disallowing cocaine's effect profile, through 'edging it out' as it were.)
It seems that this allosteric modulator of amphetamine-subjected DAT has the capability to slow the uptake of dopamine back into DAT, which amphetamine itself doesn't do as a consequence of its manner of phosphorylating DAT to instigate a cascade/release (this being the repercussion whence amphetamine renders the symporter function of DAT to anti-porter like status).
The 'agonist-like' allosteric modulators, which additionally slow release, seem have their legitimate uses sought as a basic medicinal answer for their dopaminergic 'extended release' prospects. Which may anticipate a capacity for alleviation of certain cognitive disorder symptoms, and doing so without perhaps an overweening measure of dopaminergic activity/stimulation. As that might otherwise lead to being not well tolerated, as amphetamine is sometimes not. If such aspects were able to be excluded from the current profile of side effects in amphetamine, as sleeplessness, or even the risk of habituation, it would be a boon to the portfolio of the company that were able to derive a new formulation from it.
Being that I am me, I had to make a
Wikipedia article on the antagonist
