Molecular symmetry, to indicate combination potential of drugs?

[JohnBoy2000]

This may sound like a far reaching theory but - I'm a firm believer in patterns.

Patterns of the universe, mathematical patterns, behavioral patterns etc - Fibonacci series is the one we're probably most familiar with.
Mathematicians have long since been attempting to determine patterns in the stock market.

Again - there's specifically no scientific data to document this in relation to pharmacology but - I've been using a combination of Atomoxetine and Mianserin to provide the most potent noradrenergic boost.

Subsequently - I have been attempting to introduce a serotonergic component via an SSRI/NRI type of drug - with limited success.
This is mainly due to their poor ability to combine well with the former two.

As Mianserin and mirtazapine basically have the same interaction profile - I thus attribute it to poor interaction potential with Atomoxetine - as SSRI/NRI's are well documented in combination with mirtazapine.


The only two large scale trials on Atomoxetine in combination has been with Sertraline, and fluoxetine.

I have attempted;

- Venlafaxine
- Escitalopram
- Sertraline
- Duloxetine
- Desvenlafaxine
- Brintellix

... as potential agents.
The closest I came was with Sertaline - and to a far lesser extent, Duloxetine.

I selected these on the basis of their CYP inhibition profiles (being low), as Atomoxetine is highly sensitive to CYP2D6 inhibition.

However - a very prevalent side effect - was excessive sweating.
This indicates to me, a highly taxed central nervous system.


Additionally - over the course of 24 hours - the best results were always had dosing, in between Atomoxetine and Mianserin - as I would normally dose these about 8:00, and 22:00.
So somewhere around 16:00 for the third agent.

This would suggest sufficient metabolic time for each agent.


My most recent attempt - has been with Fluoxetine.

I selected this as, looking for some kind of symmetry or pattern relative to the other two drugs - which I had previously sought in terms of the pharmacological profiles - unsuccessfully.

I figured - perhaps it would be less taxing on the CNS, to add a drug with similar structural profile, in terms of its molecular make up - regardless of its ultimate pharmacological effect.

As three anti-depressants in combination is quite unusual - effectively attempting to scale back the "heavy'ness", of the approach, by having only slightly molecular disparity between two of them.

In this case - Atomoxetine and Fluoxetine - both being highly similar.

Fluoxetine

Atomoxetine - basically subbing the tri-fluoride ring for a carbon.


I'm on day 3 of this - and it's been the first drug I've taken in combo, that hasn't resulted in catastrophic sweating - so that's good.

I've upped the dose just now to 40 mg - as 20 mg falls below the standard 80% 5HTT occupancy.


Does this approach carry any merit?

Perhaps difficult to comment on as - it's certainly not been documented but - none the less.

 

[JohnBoy2000]

Dammit - can a moderator please move this to the neuroscience and pharmacology subforum??

 

[sekio]

perhaps it would be less taxing on the CNS, to add a drug with similar structural profile, in terms of its molecular make up - regardless of its ultimate pharmacological effect.

If anything, structure matters less than pharmaceutical activity, how the molecules "look" as 2d structural formulas is not necessarily a good representation of how they are in 3d space nor how they interact with varying proteins.

What are you trying to do anyway? "Stimulating norepinephrine" is very nonspecific and there are many agents that could be classed as doing such, from a_2a antagonists like yohimbine, to amphetamine-type stimulants, to NRIs/SNRIs/triple reuptake inhibitors.

Part of the reason doctors don't diagnose "low norepinephrine" is because it almost always can be viewed as symptoms that commonly respond to NE-ergic treatment... daytime sleepiness, AD(H)D, depression, etc. - and that tends to be more specifically useful because the symptoms do not always present as a humongous cluster (e.g. hypersomnolent depressed ADHD patients with motor tics...)

The trend in modern pharmacy tends to be towards taking one drug that hits two targets rather than two drugs that hit two targets, just to remove one more set of variables from the equation and make the doctor's (and patient's) life easier.

So my advice would be, if atomoxetine doesn't do what you want and you think adding serotonin reuptake ability, consult a chart and pick a SNRI with suitable ratio of efficacy at 5HT:NE, then go from there.

 

[JohnBoy2000]

If anything, structure matters less than pharmaceutical activity, how the molecules "look" as 2d structural formulas is not necessarily a good representation of how they are in 3d space nor how they interact with varying proteins.

Well - that had been the premise I had been operating on; pharmaceutical activity taking priority - but I just wasn't getting results.
It's like - Atomoxetine was just rejecting the combination drug.

The structure may not be a good predictor of pharmaco activity - and I suppose that's where I gets a little hazy.

My contention was - perhaps it was taxing on the body to metabolise three potent agents, that were so very different; heavy on the CNS.

My logic was simply - reduce the disparity in so far as possible.

And thus far - the main facet of change I've notice is - less sweating.
Still some - but less that with others.

Perhaps indicative of things being a little easier on the CNS?

What are you trying to do anyway? "Stimulating norepinephrine" is very nonspecific and there are many agents that could be classed as doing such, from a_2a antagonists like yohimbine, to amphetamine-type stimulants, to NRIs/SNRIs/triple reuptake inhibitors.

​

Stimulate NE, therapeutically, exclusively.
Not via drugs of abuse.
Sure - amphetamine could crank it up - but with the known consequences.

In terms of use of licenced anti-depressants, to increase NE, in sustained manner.
And then - to make the addition of a serotonergic component.

Part of the reason doctors don't diagnose "low norepinephrine" is because it almost always can be viewed as symptoms that commonly respond to NE-ergic treatment... daytime sleepiness, AD(H)D, depression, etc. - and that tends to be more specifically useful because the symptoms do not always present as a humongous cluster (e.g. hypersomnolent depressed ADHD patients with motor tics...)

The trend in modern pharmacy tends to be towards taking one drug that hits two targets rather than two drugs that hit two targets, just to remove one more set of variables from the equation and make the doctor's (and patient's) life easier.

So my advice would be, if atomoxetine doesn't do what you want and you think adding serotonin reuptake ability, consult a chart and pick a SNRI with suitable ratio of efficacy at 5HT:NE, then go from there.

There are some drugs that are SNRI's - but the equivalent receptor occupancy for NE is pathetic.

With Atomoxetine - receptor occupancy is, 100% (via PET studies).

The closest SNRI would be the one from fibromyalgia - Fetzima - which has about 40% NET occupancy.

And what was most notable to me when I commenced Atomoxetine, even at the lowest dose - was a tremendous improvement in peoples response to me.

When I took Duloxetine by example - there was an improvement in one sense - and dramatic disimprovement in another sense.


Again - this is not pharmacological terminology but - I've began to regard this as, each drug having it's own, "personality", of sorts - and taking said drug, will augment the users personality accordingly - such being my contention.

What I'm thinking is - this personality is perhaps somewhat relative to pharmacological profile - but now I'm beginning to believe, also intrinsic as to its actual molecular architecture - bizarre as that may sound.


So far - it's not bad, maybe too early to tell (atomoxetine + fluoxetine together).

One thing though - I'm effectively chemically castrated.

Bummer.

I'm trying to look at oxytocin or melanotan or something to assist with that.

 

[Hodor]

My contention was - perhaps it was taxing on the body to metabolise three potent agents, that were so very different; heavy on the CNS.

This logic is, unfortunately, flawed.

Compounds that are closely related in structure are more likely to compete for the same enzymes.
It is therefore more likely that the more different they are, the *easier* they are for your body to process, i.e. they are less likely to potentiate each other in unpredictable ways, or (theoretically) lead to the overproduction of toxic minor metabolites due to the saturation of the primary metabolic pathway.

However, that usually isn't a concern at therapeutic dosages.

At any rate, I would advise against injecting melanotan (or any other peptides from shady Chinese labs, for that matter)...maybe you could get a prescription for a low-dose dopamine agonist (ex.: pramipexole), and/or drop the dosage on your serotonergic antidepressant a bit.

But IMO you are really overthinking the whole thing, and might actually be falling victim to nocebo effects... psychopharmacology is, to some extent, still trial and error.

 

[JohnBoy2000]

This logic is, unfortunately, flawed.

Compounds that are closely related in structure are more likely to compete for the same enzymes.
It is therefore more likely that the more different they are, the *easier* they are for your body to process, i.e. they are less likely to potentiate each other in unpredictable ways, or (theoretically) lead to the overproduction of toxic minor metabolites due to the saturation of the primary metabolic pathway.

However, that usually isn't a concern at therapeutic dosages.

At any rate, I would advise against injecting melanotan (or any other peptides from shady Chinese labs, for that matter)...maybe you could get a prescription for a low-dose dopamine agonist (ex.: pramipexole), and/or drop the dosage on your serotonergic antidepressant a bit.

But IMO you are really overthinking the whole thing, and might actually be falling victim to nocebo effects... psychopharmacology is, to some extent, still trial and error.

Structurally similar - competing for the same enzymes; If we're talking CYP category - 2D6 is the primary consideration with the majority of drugs from the AD class - and while fluoxetine is a strong inhibitor of this enzyme, and atomoxetine, it's structural analogue, highly metabolized by it; for whatever reason - I'm not getting a fraction of the side effects I experienced with non-structural analogues in combination.

There was one large scale trial with this combo, and their contention was, "we hypothesized this fluoxetine would combine well with atomoxetine", but didn't go into further detail as to why they selected fluoxetine out of the SSRI class.


I'm also thinking of it like - each drug, therefore, each structure - has it's own personality.

The more varying the structure, the more varying the personality - so it was perhaps like, the users personality is pulled in too many different directions to ultimately be tolerable.

I'm not a pharmacologist, so I don't really know but - despite the obvious enzymatic interaction here - the actual tolerability is, thus far, superior to any other combination drug I've tried.

Now - obviously someone running clinical trials had "hypothesized" the same thing - but unfortunately, they kept their rational to themselves.


Outside of fluoxetine - fluvoxamine was the only remaining drug possibility - but I am very unfamiliar with this drug, and understand it can be quite sedative??
It also elevates plasma levels of mirtazapine/mianserin - but there's been no explanation as to the clinical outcome of this.

I experienced a protein binding displacement interaction previously with Mianserin and Reboxetine - where I had to cut the mianserin dose in half, due to them both being highly bound to alpha 1 acid glycoprotein.
Would an interaction based on CYP inhibition yield a similar outcome to protein binding displacement??
More unbound drug - versus higher exposure??

 

[Pomzazed]

Look at 4D structure of molecules (3D plus how much it can wiggle), if you can’t, look at 3D one

2D structure only shows connectivity of atoms but doesnt show true shape and size.
What are you looking for is not just a random theory, take this keyword: QSAR
(Quantitative Structure-Activity Relationship): it is a well established scientific method.

Focusing on shape, size, dimension, also specific things like electron density of each part of molecules,
partial charge, etc. and find the relationship between those and the interested activity

 

[Coolwhip]

What are you looking for is not just a random theory, take this keyword: QSAR
(Quantitative Structure-Activity Relationship): it is a well established scientific method.

Except he's not trying to find molecules with similar action, he's picking drugs with known action and applying some kind of perceived synergy because it makes him feel better that their 2D models look similar. I'm sorry but I am going to be blunt, even if your theory held true to 3d models, it's just coincidence. The only thing that matters is activity and kinetics.

When one prefers one structural class of drugs over another it is often because their activity is similar, but when you are talking about drugs with completely different targets it doesn't matter. Their similarity could still impact treatment as far as their kinetics but you seem determined to attribute synergy to some unquantifiable characteristic resulting from their similarity that is independent of activity or kinetics; and until I see something empirical which changes my worldview, that's just nonsense. I'd sooner believe that you have some sort of OCD and their perceived symmetry truly impacts your psyche.

 

[Pomzazed]

, but when you are talking about drugs with completely different targets it doesn't matter. Their similarity could still impact treatment as far as their kinetics but you seem determined to attribute synergy to some unquantifiable characteristic resulting from their similarity that is independent of activity or kinetics; and until I see something empirical which changes my worldview, that's just nonsense.

Hmm.. true, When i posted I just skimmed through the content but didnt carefully read it

 

[JohnBoy2000]

Except he's not trying to find molecules with similar action, he's picking drugs with known action and applying some kind of perceived synergy because it makes him feel better that their 2D models look similar. I'm sorry but I am going to be blunt, even if your theory held true to 3d models, it's just coincidence. The only thing that matters is activity and kinetics.

Well, that's the point that surprised myself.

I had previously considered activity and kinetics to be the only factors that could affect combinability.

Having cycled through about 7 agents, several of which I had tolerated well in monotherapy previously - they were all soundly rejected, and they all made me sweat like crazy.

I get it sounds unorthodox but, like I said - I truly believe in symmetry, in patterns.
The universe is based on it.
True random does not exist.

So despite the failings of those other 7 agents which - based on activity and kinetics, should have combined well - I believed soundly, an agent that would offer good combination potential was there to be had.

Then it occurred to me, the greatest source of symmetry between the drugs - their actual structure (and yes, 3D/4D of atomoxetine and fluoxetine is almost identical - save for the trifluoride ring).

Low and behold - they combine - no sweating.

They work together.

When one prefers one structural class of drugs over another it is often because their activity is similar, but when you are talking about drugs with completely different targets it doesn't matter. Their similarity could still impact treatment as far as their kinetics but you seem determined to attribute synergy to some unquantifiable characteristic resulting from their similarity that is independent of activity or kinetics; and until I see something empirical which changes my worldview, that's just nonsense. I'd sooner believe that you have some sort of OCD and their perceived symmetry truly impacts your psyche.

I'm purely speculating here but - likening structural classes to activity is a little off, no?

Across the range of tricyclics - all structurally similar - but some NRI's, some only SRI's, the activity varies widely.

However - regardless of activity and/or kinetics - tricyclics are all reputed to be effectively "heavy duty", carry sedation, higher risk in overdose etc.

This is a similarity, obviously independent of activity and/or kinetics.

It is obviously relative - to chemical structure - at least, that's my current thinking.
I'm not a pharmacologist, nor a chemist.


I'm not sure it's correct to say an "unquantifiable characteristic".

Do we know how exactly the molecules tumble through the nervous system?

The characteristic is obviously their structure.

But, "change my worldview" - well, it has in fact, actually changed my world view.
It's something I had never conceived of, not even remotely considered.
Is there empirical data to support this revolutionary view?
Well - not really.
But it has been my experience - and logically - it had been my deduction.


As a final point - I have a friend who banged himself up in several car accidents, so he takes Tramadol, chronically.

The anti-depressant to which he responded best - was Venlafaxine.

Their activity and kinetics so hella different - but their structure is again, highly similar.

To me it's, an obvious and, until now - overlooked - pattern, an overlooked symmetry; and that is crucial.


So with all that being said - dosed 80 atomoxetine, 40 fluoxetine this morning - had a great day, no excessive sweating - unquestionably the best combination I've had with atomoxetine thus far.
Tomorrow, I up fluoxetine to 60, and await results.

 

[JohnBoy2000]

Just out of curiousity also - is the max dose for fluoxetine typically 80 mg, or 60 mg??

 

[Hodor]

I'm purely speculating here but - likening structural classes to activity is a little off, no?

Across the range of tricyclics - all structurally similar - but some NRI's, some only SRI's, the activity varies widely.

However - regardless of activity and/or kinetics - tricyclics are all reputed to be effectively "heavy duty", carry sedation, higher risk in overdose etc.

This is a similarity, obviously independent of activity and/or kinetics.

It is obviously relative - to chemical structure - at least, that's my current thinking.
I'm not a pharmacologist, nor a chemist.

I'm not sure it's correct to say an "unquantifiable characteristic".

Do we know how exactly the molecules tumble through the nervous system?

The characteristic is obviously their structure.

The sedation produced by the tricyclics is the result of their activity as antagonists of histaminergic, adrenergic and serotonergic receptors. The risk of overdose comes from their activity as antagonists of acetylcholine receptors.
This is well known, not a mystery.

As a final point - I have a friend who banged himself up in several car accidents, so he takes Tramadol, chronically.

The anti-depressant to which he responded best - was Venlafaxine.

Their activity and kinetics so hella different - but their structure is again, highly similar.

To me it's, an obvious and, until now - overlooked - pattern, an overlooked symmetry; and that is crucial.

Tramadol is an SNRI and an opioid.
Venlafaxine is also an SNRI.

Not exactly "hella different".

What you discovered is just the placebo/nocebo effect. No, even as a knowledgeable person, you are not immune it to it. Especially if you are a person who's naturally primed to look for patterns.

Also, please don't say "trifluoride ring". It's called a trifluoromethyl group. It can't be a "ring" if it's not cyclic.

 

[Hodor]

Just out of curiousity also - is the max dose for fluoxetine typically 80 mg, or 60 mg??

Google says it's 80mg. Some psychiatrists may be willing to go beyond that, but usually they'll just switch you to a different antidepressant (or add another ned) if 80mg isn't working out for you.

 

[adder]

There may be many different reasons (pharmacologically) why atomoxetine+fluoxetine doesn't produce sweating unlike atomoxetine+SSRI/SNRIs you mentioned. The fact is that it's fluoxetine that you tolerate better than all the other SSRI/SNRIs. But there is no ground for jumping at conclusions that you did. Each of these antidepressants aside from inhibiting 5-HTT (and NET) interact with several secondary and tertiary targets, their metabolites may also be more or less important in the overall pharmacological profile of effects which is very complex.

Think about the structural similarity of atomoxetine and fluoxetine and their vastly different pharmacodynamics, one being classified as NRI and the other as SRI. If your simple theory had any merit (i.e. structural similarity means similar tolerability as I understand it), then you would also expect that these two drugs would be very close in their pharmacodynamics, yet just the ring substitution pattern is enough to eradicate affinity at SERT and give affinity at NET. There is no basis to link structural similarity to tolerability, there is also no basis to link structural similarity to pharmacodynamics. You seem to forget that these molecules interact with receptors which are large protein molecules and can adopt many different conformations, for them to bind ligands structural similarity is not important at all but whether the incoming molecules have in their structure moieties with specific electronic and steric properties at specific distances between them to interact with specific aminoacid residues in the receptor part of the protein. Such binding can be achieved with structurally different compounds.

Looking at it from this perspective my conclusion would be that judging drugs solely based on structural similarity can be very misleading without proper SAR data and preferably information about the receptor cleft itself.

 

[checktest]

Going off of a similar structural motif, 6-OH dopamine should be comparable/tolerable for low blood pressure treatment in the hospital, relative to dopamine. 'Only' a hydroxyl group difference. Or say, 8-OH dopamine. Isomers, let alone small structural differences, can have marked changes in pharmacological properties, switching agonism to antagonism. CFC shared an adrenergic pharmacology link that highlights the significant differences and interaction between epinephrine and norepinephrine, as an example. Look at some of the opioid derivatives, antagonism, partial agonism, agonism. While structural similarity can be a guide for drug development, what actually happens in vivo is more complex. Especially in dealing with large, multi-conformational receptors and dynamic systems.

80 mg is a typical max for fluoxetine, though some prescribers use higher doses in OCD. I was on fluoxetine and desipramine. It can be tempting to find and believe in patterns, we are hard-wired to do so and there is intuition from it, it doesn't mean they are an exact reflection of reality or significant.

 

[Coolwhip]

Then it occurred to me, the greatest source of symmetry between the drugs - their actual structure (and yes, 3D/4D of atomoxetine and fluoxetine is almost identical - save for the trifluoride ring).

Low and behold - they combine - no sweating.

That's half the problem...just the fact that you thought their "symmetry" would cause said combination to produce the effects you are looking for is enough to affect the outcome. This is not something that should be written off or overlooked.

If we were to disregard this fact, and assume that your expectations aren't playing any role here, then this would just be a coincidence, or there is some pharmacological explanation which explains it which is being overlooked but that explanation would be a result of activity which is related to structure, but it wouldn't be because of structure independent of activity.

likening structural classes to activity is a little off

No, see Pomzazeds's post about SAR. And Hodor pretty much already answered this, but tricyclics have LOTS of off-target activity, which is why they come with so many shared side effects, as said before they have these commonalities because they have similar activities because they have similar structures. You can guess the activity of a substance based off its structure(SAR), but structure alone is neither a cause of nor responsible for any of a drug's effects.