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Alpha 1 antagonism, coupled with Alpha 2 antagonsim

JohnBoy2000

JohnBoy2000

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I had read pieces of information on the effect of this at some point but, haven't since been able to find any concrete information in texts, papers etc.

What I'm trying to do is understand the exact differences between Mirtazapine, and its analogue, Mianserin.

Mirtazapine lacks Alpha 1 antagonism, but has a stronger Alpha 2 binding.
Alpha 2 being responsible for the release of noradrenaline and serotonin.

Now - Mianserin is known to act solely on Noradrenalline, not serotonin - unlike Mirtazapine.

What I had read at some point was that the Alpha 1 antagonism is responsible for mitigating mianserins effect on serotonin.
But like I said, I haven't found any data on wikipedia, or in pharmacology texts, supporting this.

I guess - is this the case/true?

Why does mianserin implicate only noradrenaline, not serotonin.

It's clinical effect would suggest it is a much more potent noradrenaline implicator than mirtazapine - as a result of the increased degree of activation.
I assume in vivo studies have demonstrated this to be the case also.

But from a pharmacodynamic point of view - which of its actions is responsible for this - most importantly, it's lack of serotonergic effects?
 
It could be that there is a high degree of potentiation of whatever NE is released via a2 blockade with NRI, while the SRI is fairly low. So in other words if the SRI and NRI affinity of Mianserin was reversed, it could be predominantly serotonergic.

But has it been shown that mianserin is primarily noradrenergic? Even NRIs are shown to increase serotonergic activity and release. Serotonin, dopamine and NE are all highly interrelated. Even dopamine reuptake inhibitors can decrease serotonin reuptake a fair bit.
 
This is too confusing
Mianserin
Binding profile Edit
Molecular target Binding affinity (Ki [nM])[23]
SERT 4000
NET 71
DAT 9400
5-HT1A 1500
5-HT1F 12.6
5-HT2A 3.21
5-HT2B 10.9
5-HT2C 2.59
5-HT6 68.1
5-HT7 56
α1 adrenoceptor 74 (Cloned rat receptor)
α2A adrenoceptor 4.8
α2B adrenoceptor 27
α2C adrenoceptor 3.8
D1 receptor 923
D2 receptor 2052
D3 receptor 2841
H1 receptor 1.0
H4 receptor 750

Mitrazapine

Molecular target Binding affinity, Ki (nM)[83] Notes
5-HT2A receptor 69 The (S)-(+)-enantiomer is responsible for this antagonism.[8]
5-HT2B receptor ? ~20-fold lower than for 5-HT2A/5-HT2C[84]
5-HT2C receptor 39 Inverse agonist[85] The (S)-(+)-enantiomer is responsible for this action.[8]
5-HT3 receptor ? Similar to 5-HT2A/5-HT2C (mouse neuroblastoma cell)[86] (R)-(–)-enantiomer antagonises the 5-HT3 receptor.[8]
5-HT7 receptor 265
α1 adrenergic receptor 500 [87]
α2A adrenergic receptor 20 The (S)-(+)-enantiomer is responsible for this antagonism at autoreceptors.[8] Heteroreceptors are blocked by both the (S)-(+)- and (R)-(–)-enantiomers.[4]
α2C adrenergic receptor 18 The (S)-(+)-enantiomer is responsible for this antagonism at autoreceptors.[8] Heteroreceptors are blocked by both the (S)-(+)- and (R)-(–)-enantiomers.[4]
D1 receptor 4167
D2 receptor >5454
D3 receptor 5723
H1 receptor 1.6 [88]
mACh receptors 670 [87]

The lower the number the higher the affinity. 5ht stands for 5 hydroxy tryptamine which is a synonym for seritonin. Therefore both compounds influence seritonin by binding to seritonin 2a and c receptors these are seperate from the seritonin transporter. The seritonin transporter is on the presynaptic neuron and blocking its ability to reuptake serotonin increases the amount of seritonin to bind to 5 ht receptors. The 5 ht 2 a and c down regulate from both agonists and antagonists. Therefore, both via inhibition of a sert transporter by prozac increasing the amount of seritonin in the synaptic cleft to bind to 5 ht2ac receptors and these two compounds via acting as a ligand acting as a ligand that is a antagonist that is able to act like seritonin fit into these5 ht2ac receptors acting functionally as a a agonist duebto these receptors paradoxically downregulating despite them behaving as antagonist.

Strattera has a affinity for the net of 5 which is over one order of magnitude (10 fold) than misanerin therefore, id guess that the action of both compounds is primarily via there ability to act like norepinephrine as inactive plugs on autoreceptors allowing more morepinephrine post synaptically to adrenic 2 receptors rather than acting on the norepinephrine transporter.

In short, mianserin and mitrazapine appear to be nearly identical influences norepinephrine via alpha 2 adrenic receptors and seritonin via 5 ht 2 receptors. I am doubtful a binding affinity of 70 nm is significant to consider mianserin active at th net. The sert and net transporters influence the amount of seritonin and norepinephrine available to bind to alpha adrenic and 5 ht receptors respectively. 5 ht is a synonym for seritonin and norepinephrine for noradrenaline.
 
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Copied from dr-bob:

Maybe the easiest way to describe mianserin is by comparing it to mirtazapine.
Mirtazapine and mianserin are both tetracyclics. At a glance they seem almost identical, mostly due to their similar side-effect profile (sedation from H1 antagonism and -usually- appetite increase, most likely caused by 5-HT2C and 5-HT2A blockade).
They're both classified as "NaSSas": "noradrenergic and specific serotonergic antidepressants", but that's a bit inaccurate.
They're actually very different.
They both block alpha 2 adrenergic presynaptic
receptors, which increases norepinephrine (noradrenaline) neurotransmission. Very, very strongly.
But additionally, mirtazapine (but not mianserin) also blocks alpha 2 adrenergic presynaptic receptors on *serotonin neurons*, boosting serotoninergic neurotransmission. Mianserin's effect on these receptors is negligible.
So, basically, mianserin only pushes noradrenaline release and Remeron boosts both noradrenaline release AND serotonin release.
But that doesn't necessarily mean that Remeron is "better" than Tolvon (mianserin), they're just different. Mianserin inhibits norepinephrine reuptake, whereas Remeron has no known reuptake inhibition properties. Also, Tolvon has a much stronger / tighter binding affinity to most, if not all, of its targets compared mirtazapine, so you could say that it's more "powerful" in a way. It certainly acts faster (and mirtazapine itself is no slug).
There are lots of additional differences, I just mentioned the main ones.
They're definitely not interchangeable.
The beauty of these drugs is that they hit a whole bunch of "useful" receptors (and, even though they've been around for a while, the list of newly discovered pharmacological effects keeps growing) yet they are extremely clean.
Anyway, in practice:
Remeron might be underdosed in the US, which is probably why it's not all that popular. Maybe that's why it doesn't help your depression? In Europe and other areas, the max dose is 90mg versus 45mg in the US (and going up to 120mg is not unheard of). In most cases, the NE boosting action only just begins at 45mg, so chances are that you're not getting its dual action at 30mg (and certainly not at 15). Still, at 30mg the serotonin boost is very powerful, and that's why it can augment reuptake inhibitors very nicely. Whatever NE action that might be happening at the lower doses is usually drowned out by the flood of serotonin (soothing). I've gone up to 60mg Remeron and the only way I could tolerate it was with benzos onboard, starting at 45mg the amount of agitation and activation I got was downright scary. No sleepiness, no hunger.. It most definitely zapped my depression though, within days.
Mianserin is a whole different animal. I think that the max rec. dose is 90mg "worldwide". As mianserin doesn't push serotonin (kindof), all you get is raw NE action. I know that the following equivalence is totally incorrect, but the way it feels is 30mg mianserin = 45 mg remeron. 60mg mianserin (usual dose) = 60 mg Remeron. I have no idea how some people manage to tolerate the max dose of 90mg mianserin. BTW, IME mianserin's one big drawback is the soporific antihistaminic effect combined with the sheer NE activation at any dose, until I get used to this, I feel tired yet very energized at the same time, very uncomfortable.
I didn't even go into different 5-HT2C actions and the remaining boatload of additional targets and effects they have.
They're definitely very complex meds... and taking the proper dosage is everything, depending on how much you take you'll get totally different effects.
I'll keep rambling for a bit longer:
I use them sparingly because, unfortunately, they tend to poop out very quickly. I call them my safety net, they're my reliable last resort option.
- Whenever bad anxious depression strikes, it's Remeron 30mg. Helps a ton. Good sleep, mood brightening etc. I've only felt suicidal once during my screwy mental health career, and the 60mg dose pulled me out just in time... Might have just saved my life. But very hard to tolerate.
- Conversely, when bad anhergic depression strikes, just mianserin 15mg helps a lot. I usually start out at 30mg and quickly lower the dose to 15mg as soon as the most troublesome symptoms resolve as, despite the H1 sleepiness, I find it extremely activating.
As usual YMMV. Maybe the mianserin will glean no benefit for you... we all have different biochemical makeups of course so.. I hope this post is helpful, any questions just ask away.
Ok, enough with my Ode to Organon.

d1nach - I came to similar conclusions after reading wiki but - it appears there's more there than meets the eye.

Whoever wrote the above piece - I'd like very much to know where they got that info.
 
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He seems kind of coffee shop neurosciency, which I am guilty of to some degree but he seems moreso guilty.

Take for example "But additionally, mirtazapine (but not mianserin) also blocks alpha 2 adrenergic presynaptic receptors on *serotonin neurons*, boosting serotoninergic neurotransmission. Mianserin's effect on these receptors is negligible."

This would imply that the difference in NE vs. 5-HT between mirtazapine and mianserin is due to differential affinity of a2 subunits, I believe there is a2a and a2c. Other than that there is no way to explain this statement. But considering that mianserin is an NRI while mirtazapine is not inhibiting reuptake, there is no need to invoke differences in a2 antagonist enhanced pre-synaptic efflux of neurotransmitters to explain why mianserin might have more NE effects.

Whatever NE is already in the cleft is going to be magnified by NRI. So I don't think its necessarily that there is more presynaptic autoreceptor blockade facilitated efflux of NE vs. 5-HT, but rather whatever efflux there is, the NE efflux is really potentiated by inhibiting the clearance of NE from the synapse with NRI. So if you switched mianserin's reuptake inhibiton and it was inhibiting SERT instead of NET, then it could be primarily serotonergic.
 
^^ By that logic would making the addition of an NRI to mirtazapine effectively result in a similar efficacy, as if mianserin was already in place.

As, by your description - the only difference between mianserin and mirtazapine would be the very mild NET binding of 71 nM.
But say there was a drug already implimenting NET binding - desipramine, just say for example - then the efficacy of the drug combo would theoretically not be enhanced by replacing mirtazapine with mianserin - as the NRI property is already there.

The other element to consider is mianserins alpha1 binding being appreciable compared to mirtazapines negligible value.
How alpha 1 affects noradrenaline - I'm not sure - though it's antagonism is associated with sedation and orthostatic hypotension.


All that being said - the poster of that piece claims anecdotally that it is much more activating than mirtazapine, and "feels" is is more noradrenaline based.
Which given the paucity of information on mianserin out there - is at least some insight - though questionably reliable of course.
 
Atomexetine + mirtazapine for example, but it's really nice to have effects tied in to one medication because of pharmacokinetics. You generally want a pretty stable half life.

The other thing to take into account is that mianserin appears to have much more antagonism of 5-HT2C, receptors that normally inhibit NE neurons. So once again you have a multitude of effects potentiation NE release - reduced autoreceptor inhibiton of NE neurons, reduced 5-HT2C mediated inhibiton, and NRI.

I would make the case that if mianserin is more NE, it's due to the NRI and 5-HT2C relative to mirtazapine rather than differential affinity for a2 subunits, although I'm certainly open to the possibility that it's moreso due to a2 subunits having different expression on different cell types but I haven't seen, nor looked for evidence of that.
 
I'm just gonna post bits and pieces of information from different studies as I go, to try and build sense of the picture.

"Mianserin failed to affect serotonergic transmission inclear contrast to mirtazapine. This is attributed to the 10-foldhigher affinity of mianserin for alpha-i adrenoceptors, whichprobably prevented the NE-mediated enhancement of serotonergictransmission. "

http://jpet.aspetjournals.org.sci-hub.cc/content/277/2/852.long
 
Brilliant paper unfortunately they seem much smarter then me so ill try to read it later after this play I have to attend. I dont see how a 70 nm binding affinity is significant though at blocking net. Is it possible a secondary metabolism of mianserinhas more net affinity
 
Yeah it's hard to locate the good papers.
Don't even know where I found that one - just had it bookmarked from several weeks ago.

I must try google scholar.
I've heard that can be good at sorting through the muck.
 
The Ki of mianserin for NET (70 nM) could definitely be therapeutically relevant. The following study suggests that bloods levels are often in the 100 nM range after a few weeks of therapy. Although that isn't necessarily the level in the CNS, it wouldn't be suprising if the level in the brain was in that range.

http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2125.1978.tb04573.x/abstract
 
I came across a paper before that clearly stated:

Mianserin - implicates solely noradrenaline
Mirtazapine - implicates NA and serotonin.

I also read somewhere that, there was speculation that mirtazapine more potently implicated noradrenaline than mianserin...?

That doesn't really make sense, does it?
 
JohnBoy2000 said:
http://jpet.aspetjournals.org.sci-hub.cc/content/277/2/852.long
Click to expand...

Just to clarify, I think what this study is saying is that the a2 antagonism increases NE which increase 5-HT via a1, but with higher a1 blockade (mianseirn) the 5-HT portion a2 blockade is somewhat negated. It appears however that this study is dealing specifically with the hippocampus. I still would've have liked to have seen them control for the NRI, maybe adding in a mirtazapine + a selective NRI that achieves roughly the same degree of occupancy of the NET as mianserin at a similar level of a2 blockade.
 
Hmmm if 80 nm is active at net and 5nm for strattera is active net is mianserin dose in the hundred of mg ?
 
Im getting lost here maybe you might be better off like getting a paper folding it in half and having where the chemical directly influences something on one side and where its indirect on the otherside. Otherwise you could just get people saying does caffeine interact with dopamine? Some saying yes because it indirectly influences dopamine. Some saying no because it doesnt directly bind like cocaine to the dat transporter.
 
You could say then that mirtazapine is directly blocking a2 receptors located on cells that release NE, this results in increased release of NE that binds post synaptically to a1 which mediates downstream 5-HT release. Mianserin differs in that it blocks the a1 receptor directly (as well as inhibits NET and blocks 5-HT2C more potently).

I think one confounding issue is co-release, the notion that some cells release more than one neurotransmitter. I'm not well read on this subject but it's possible that mianserin is still increasing 5-HT somewhat appreciably by binding to a2 located on seotonergic cells, or on noradrenergic cells that corelease serotonin.
 
^^ Well in hoping to answer that question - there was a study that had the data from EEG or PET scans or something of that natural - that clarified mianserin, in vivo, acting purely on NE - mirtazapine acting significantly on both.

I'm pretty sure it's the link I posted above, but for whatever reason, scihub unlocked it previously, but won't unlock it now.
 
Nope - didn't actually have that info in that particular paper but - another paper on the pharmacology of mirtazapine, drew the comparison to mianserin:

Mirtazapine is chemically very similar to another
antidepressant, mianserin, the drug that first raised
the possibility of a,-adrenoceptor antagonism as
a therapeutic mechanism. However in contrast
to mirtazapine, mianserin does not increase 5-HT
release at all. The reason for this lays in the
pharmacology of mianserin; it has significantly
greater a,-adrenoceptor-blocking properties than
mirtazapine. This means that in doses that stimulate
presynaptic release of noradrenaline mianserin
simultaneously blocks the a,-adrenoceptors on the
raphe cell bodies, thus preventing stimulation of
the raphe neurons (5). By refining the chemical
structure of mianserin to significantly decrease a,-
adrenoceptor antagonism, an agent with dual
rather than single transmitter action has been
produced. Therefore, mirtazapine can be described
as a noradrenergic and specific serotonergic antidepressant
(NaSSA).
 
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