Venlafaxine (Effexor) similar in structure to Tramadol

[punkftl]

according to Wiki...Effexor has a similar chemical structure to the opioid derivative Tramadol. it acts as an agonist at the mu-opioid receptor.

could this explain why Effexor has some of the worst withdrawals of any antidepressant? usually antidepressants with the shortest half-life have the worst symptoms, but even Effexor XR, with it's longer half-life compared to immediate release Effexor, have almost the same severity.

AND Effexor is more effective in treating depression in heroin and other opioid dependent individuals. even though i am on 400mg. Wellbutrin SR. daily along with Methadone and that seems to work well also (combined with L-Tyrosine,
5-HTP, high doses DHA fish oil)


from Wiki
Venlafaxine (Effexor, Efexor) is an arylalkanolamine serotonin-norepinephrine reuptake inhibitor (SNRI)[2]. It has a similar chemical structure to the opioid derivative tramadol, and has the tertiary amine functional group necessary for µ-opioid receptor recognition (cf. lefetamine), and indeed, Venlafaxine acts as an agonist at the mu-opioid receptor. [3] [4]It is surprisingly effective in treating depression in heroin and other opioid addicts compared to all other conventional antidepressants.[5].

and a study:
Venlafaxine and mirtazapine: different mechanisms of antidepressant action, common opioid-mediated antinociceptive effects--a possible opioid involvement in severe depression?
Schreiber S, Bleich A, Pick CG.

Department of Psychiatry, Tel Aviv Sourasky Medical Center, Tel-Aviv University Sackler School of Medicine, Israel.
Abstract
The efficacy of each antidepressant available has been found equal to that of amitriptyline in double-blind studies as far as mild to moderate depression is involved. However, it seems that some antidepressants are more effective than others in the treatment of severe types of depression (i.e., delusional depression and refractory depression). Following studies regarding the antinociceptive mechanisms of various antidepressants, we speculate that the involvement of the opioid system in the antidepressants' mechanism of action may be necessary, in order to prove effective in the treatment of severe depression. Among the antidepressants of the newer generations, that involvement occurs only with venlafaxine (a presynaptic drug which blocks the synaptosomal uptake of noradrenaline and serotonin and, to a lesser degree, of dopamine) and with mirtazapine (a postsynaptic drug which enhances noradrenergic and 5-HT1A-mediated serotonergic neurotransmission via antagonism of central alpha-auto- and hetero-adrenoreceptors). When mice were tested with a hotplate analgesia meter, both venlafaxine and mirtazapine induced a dose-dependent, naloxone-reversible antinociceptive effect following ip administration. Summing up the various interactions of venlafaxine and mirtazapine with opioid, noradrenergic and serotonergic agonists and antagonists, we found that the antinociceptive effect of venlafaxine is influenced by opioid receptor subtypes (mu-, kappa1- kappa3- and delta-opioid receptor subtypes) combined with the alpha2-adrenergic receptor, whereas the antinociceptive effect of mirtazapine mainly involves mu- and kappa3-opioid mechanisms. This opioid profile of the two drugs may be one of the explanations to their efficacy in severe depression, unlike the SSRIs and other antidepressants which lack opioid activity.

 

[StaySedated]

effexor is extremely weak at opioid receptors, it won't give an opiate buzz like tramadol(which sucks on its own right).

other than treating depression, i'd say it has little use for "other things".

 

[PoppyLlama]

i take effexor XR and wellbutrin as well and have withdrawn from effexor a few times before. they were the worst withdrawal symptoms ive ever had even worse than opiates for me. I couldn't move my head in any direction without it feeling like i was on the electric chair, shivering, twitching, my stomach was in a knot, diarrhea...so awful..i hated it. i didnt know/dont think it has any opioid receptor activity?
where did you hear about mirtazapene being a mu agonist? ive never heard of that before

 

[Phener]

^legend

 

[Supeudol]

^ How can you guys just delete or change facts or infoormatiom on Wikipedia? You must work there I assume?

 

[Slapdragonx]

Anyone can edit the Wikipedia.

 

[benzofan]

I admit after a period of habit (2 weeks) Venlafaxine give the same "high" sensation than Tramadol but you need to wait 3 hours with Venlafaxine for the first effects

Tramadol is OK after 30 min

You just have to find your good dosage

Withdrawal with Tramadol is more important than Withdrawal with Effexor, but again it depens on your daily dosage

 

[PoppyLlama]

wikipedia is not a legitimate source people, and i guess if you can get high off tramadol, maybe you can get a buzz of effexor but its really stupid to try to abuse and anti depressant..(no offense to those who do, but i would urge you to reconsider..)

 

[utrop]

A contact of mine who was very fond of Tramadol once gave Effexor a try, thinking maybe the highs etc will be similar. To his astonishment, his experience and what he was expecting was completely different. Trust me, it is very very far from tramadol, my friend says it's not worth it.

 

[Swarm]

Some of the bullshit that gets put on Wikipedia...

While venlafaxine and tramadol contain almost the exact same molecular components, the arrangement of these components, as you can see, is quite different. Thus, I can't really see them as being considered analogous, but perhaps "somewhat similar".

Hey, got turned onto this page after writing something on another thread. They are analogues of each other, the reason being that both molecules can take on conformations where the functional groups have the same spatial relationship to each other. I built models to verify this. I can send some pics if you like, if thats something we do on here.

Really like the pharmacology stuff you wrote btw. Peace.

 

[Swarm]

Some of the bullshit that gets put on Wikipedia...

While venlafaxine and tramadol contain almost the exact same molecular components, the arrangement of these components, as you can see, is quite different. Thus, I can't really see them as being considered analogous, but perhaps "somewhat similar".

Hey, got turned onto this page after writing something on another thread. They are analogues of each other, the reason being that both molecules can take on conformations where the functional groups have the same spatial relationship to each other. I built models to verify this. I can send some pics if you like, if thats something we do on here.

Really like the pharmacology stuff you wrote btw. Peace.

 

[Epsilon Alpha]

Pics or it didn't happen, while I can't access chemdraw on my phone I really doubt the stereochemistry is that similar for them.
Its well known that virtually all SSRI's modulate MOR function downstream somewhere or another, granted venlafaxine appears to be one of the more effective ones.

Analog doesn't always mean similar, pharmacology is full of that kind of thing. Hell, look at scopolamine vs cocaine.

 

[xvaltan]

Ciramadol's structure is a bit closer to venlafaxine, and it at least manages to be a partial agonist at mu. Not saying it means anything in relation to venlafaxine's effect on the receptor, but I always thought it was neat that a compound essentially the same (but with the hydroxy groups moved to different positions on the ring) would yield an active opioid.

EDIT: Oops, just noticed the extra carbon before the nitrogen on venlafaxine as soon as I post this

 

[Swarm]

Took some pics just now but am having trouble finding the gallery link so i wrote to admin so hopefully that'll get sorted soon enough.

 

[sekio]

How about you just use imgur like everyone else?

Those were overlaid and minimized in ChemDraw, the result looks like a sticky sphagetti breakfast. The bulk of the cyclohexane isn't located in the same place.

Sorry dude

 

[Swarm]

No thats no good for our purposes, all you've done there is show that the two molecules have different configurations. But in receptor ligand binding it is the conformation of the molecule that is important not the configurations. To show that they are analogues, or potential analogues, you need to concentrate nearly all the attention to the 3 functional groups (the ether, hydroxyl and N (CH3)2 groups). If you can use ingmur to show that there no possible conformations in which the 3 functional groups all share spatial arrangements then you have shown that the two molecules cant be analogues. That seems an odd approach so i just did the simple thing of build a model of each in which several "matching"conformations are shown to be possible. This shows that the two drugs a potential analogues only , due to fact that analogue in pharmacology is a term that is contingent on the receptor in question and specifically the spatial arrangement of its active sites, and i freely admit to not knowing the geometry of the serotonin/ opioid receptor active sites off the top of my head.

 

[sekio]

Whether or not the molecules can be wrenched into the "right" conformation to bind to the mu-OR is immaterial.

If the molecule must be in an energetically unfavourable position to bind to the mu-opioid receptor, chances are it won't.

Indeed, with a Ki of over 10 micromolar at mu OR, if it did have activity it would be comparable to codeine. Practical data supercedes any sort of SAR predictions.

 

[Swarm]

Hey Sekio, really liked your post - glad to see this discussion take a slightly more physical turn with some talk on potential energy at last.

As for the first point about energetically unfavourable conformations, if you take a look back at each molecule you'll see that each is completely saturated with the exception of the benzene ring. Now this means full rotation at each carbon - carbon single bond. Take a look at the molecules again and you'll see that theres no steric hindrance from any of the big groups (the ring systems). The functional groups on these molecules are very unrestricted.

Secondly, i want no part in the opiod receptor debate. My only concern really is with the serotonergic and noradrenergic activity that is shared by both venlafaxine and tramadol. i've never taken venlafaxine before but i've taken a lot of tramadol and am gonna be on the hunt for the roots of its serotonergic activity for some time yet as i think of it much more in terms of its serotonergic activity than its mu opioid activity and generally quite unhappy to compare it with codeine to any significant degree.

 

[Swarm]

As requested:

http://img411.imageshack.us/img411/3013/venlafaxine2.jpg


http://img52.imageshack.us/img52/4264/tramadol.jpg

I used the same sheet of paper both times as you should be able to see from the circles drawn. These circles represent the positively polarised amino acid sidechains of a hypothetical receptor. I chose a conformation where the functional groups were flat on the page in a single plain is this is the easiest to verify from a single photograph. Although you cant tell from the photos, while the two oxygens are flush with the paper, the nitrogen is about 2cm above the plane of the paper but this true for both molecules.
Yes i know i didnt include the hydrogens on the benene ring but i ran out of pieces and it wouldn't change anythong anyway.

 

[sekio]

Congratulations, now see if escitalopram fits too.

To me it looks like you've managed to find the structure of the SERT binding site

such is the problem with SAR...