How potent is Mirtazapine considered to be on NorAdrenaline - vs other tetra/triC.

[JohnBoy2000]

I've been reviewing a bit of literature on noradrenergics.

Bupropion, apparently, has only about a 30% occupancy rate on NE - obviously no direct effect on NET.

Is that to say that it's AD effect is attributable to NE inhibition by about 30% but, its overall mechanism of action still remains unknown?

Wiki is updated, claiming they found three new major metabolites for bupropion, making up 29% of the drugs metabolites.

If the former is the case, then it can't really be classed as an NE reuptake inhibitor in its entirely, can it?

 

[Cotcha Yankinov]

Do you mean to say that in vivo imaging studies have shown only 30% occupation of the NET in humans with bupropion?

SSRIs can be dosed to around 80% inhibiton of SERT, I'm sure that NETs could be fundamentally different in terms of needing a lower degree of inhibiton to mediate more drastic effects.

I think in many cases mechanisms of action are at least partially unknown. A drug could do 100 different things biologically. The first biological target we find shouldn't be assumed to be the primary mediator of all the drug's effects. You could find another drug that has effects on the same target that was discovered very first, but it could behave completely differently in real life.

But regarding the metabolites, unless they were doing direct injection into the CNS (avoiding first pass metabolism) in animals as opposed to doing oral intake PET imaging studies, they would have only observed the effects of bupropion itself. They could have needed to do oral administration with PET imaging to tell what bupropion actually ends up doing in its entirety concerning NET, but that's just measuring effects on NET inhibition.

Just as an example, you could then find what is known to be a fairly selective NET inhibitor and compare it behaviorally (in vivo) to bupropion at doses that result in similar inhibition of NET, to try to see if there is more going on than just NRI.

 

[JohnBoy2000]

Been searching for the report with that information.
Haven't found it yet but, did come across these in vitro results.

The in vitro concentrations for bupropion action at α3β4*-nAChR (IC50 = 1.8 μM) are comparable with those needed to inhibit DA (IC50 = 0.55 μM) or NE transporter (IC50 = 1.9 μM) function. In addition, the action of (2S,3S)-hydroxybupropion at α4β2-nAChR (IC50 = 3.3 μM) occurs in the concentration range needed to inhibit DA (IC50 = 0.79 μM) or NE transporter (IC50 = 0.52 μM) function

Which seems to suggest its actual NE and DA inhibition function is......... some weak shit, no?

 

[Cotcha Yankinov]

Well I'm still not very well versed on what affinity/efficacy you may need to get a biological response out of various targets. In other words, there may be vast differences in at which concentrations a ligand with the same affinity for two different target produces effects via either target. It could have the same affinity for both target but maybe one is such a key target that behavioral effects can be observed through effects on that target at a much lower concentration (given that this hypothetical ligand's affinity/efficacy for these different targets is all equal).

Bupropion and a metabolite also block 5-HT3a channels appreciably in addition to the aforementioned nicotinic channels.