imadazoline receptor type 2

[Hammilton]

Hello

Imidazoline type two receptors are allosteric sites on monoamine oxidase. They're also said to be involved in pain modulation and apparently have some central effects. Can someone offer a theory as to how this works? I mean this is an enzyme. I have a couple ideas but none satisfactory.

 

[pharmarat]

Looking at the action of MAO and that of some known I2 agonists, I would say that the imidazoline receptor, when bound to an agonist (e.g. 2-BFI), is inhibiting MAO activity, thereby preventing metabolism of serotonin, dopamine, noradrenaline etc. An increase in those neurotransmitters is going to have CNS effects in much the same way MAOIs would.

http://www.ncbi.nlm.nih.gov/pubmed/17056035

 

[Hammilton]

Except that an agonist at this site would be increasing, not decreasing MAO activity.

 

[atara]

Except that an agonist at this site would be increasing, not decreasing MAO activity.

o rly?

http://onlinelibrary.wiley.com/doi/10.1038/sj.bjp.0704579/full

Following training to distinguish 2-BFI 7 mg kg−1 i.p. from saline vehicle in two-lever operant-chambers, male Hooded Lister rats underwent sessions where test substances were given instead and the proportion of lever presses on the 2-BFI-associated lever (substitution) recorded.

2-BFI; its cogeners BU216, BU224, BU226 and LSL60101; the reversible MAO-A inhibitors moclobemide and RO41-1049; the β-carbolines harmane, norharmane and harmaline which also reversibly inhibit MAO-A, and the anti-addictive substance ibogaine exhibited potent, dose-dependent substitution for 2-BFI.

Agmatine, and LSL60125 substituted at one dose only. The reversible MAO-B inhibitors lazabemide and RO16-1649; the σ2-site ligand SKF10,047 and the I2A-site ligand, amiloride, failed to substitute. The irreversible inhibitor of MAO, deprenyl, substituted for 2-BFI while clorgyline did not.

Selegiline's putative depropargylation to d-amph should explain its substitutive potential. Otherwise if I2 is on MAO-A and substitutes for MAO-A inhibitors, it probably slows MAO-A down. Next up: antidepressant effects? Might be good if we can produce more MAO inhibition with less chance of a problem.

http://www.sciencedirect.com/science/article/pii/S0014299906010417

BU 224 and 2-BFI behaved as reversible inhibitors of both MAO-A and -B, as demonstrated by total inhibition of tyramine oxidation in human adipocytes and platelets or in liver from rats previously treated with selective MAO-inhibitors. Moreover, they weakly inhibited semicarbazide-sensitive amine oxidase.

I2-like sites are present on multiple enzymes. Of course we may not yet be convinced of the selectivity of these compounds, but the potential for MAO inhibition is clear, unfortunately it seems to be powerful enough to inhibit tyramine metabolism, which is bad. They also inhibit lipolysis in adipocytes but do not alter the progression of obesity (?).

http://www.sciencedirect.com/science/article/pii/S0014299998003896

I2 appears to have various subtypes, and currently the receptors called "I2" are grouped together for common agonism by the popular research ligands (2-BFI). Unfortunately not enough is known about where these receptors are to give even a suggestive overview of their MOA; we know norepinephrine is sort of antinociceptive, but it's a long walk from allosteric inhibition of neurotransmitter-degrading enzymes to increased NE where it counts.

 

[Hammilton]

Hmm... why would it be considered an agonist at the site if it's decreasing the activity of the enzyme. As an allosteric site, I would have thought that an agonist would upregulate activity, and an antagonist would downregulate the activity. I mean, I don't think ligands for enzymes are usually considered agonists or antagonists, but it seems backwards to me to view a ligand at an allosteric site that inhibits the activity of the primary site as an agonist. There may be a good reason that I'm unaware of.

2-BFI greatly interests me as a potentially safer alternative to direct inhibitors of MAO, which are still pretty much tops for anti depressants.