Agents with roughly equal 5HT and NE actions?

[JohnBoy2000]

Stahls book brings up more than once that, in agents where there is a dual mechanism of action, the normally requisite 90% occupancy of NE receptors required for efficacy, may be significantly reduced - due to the dual mechanisms of action.

Venlafaxine is waaay more selective for 5HT.

Desvenlafaxine?
I'm not sure.

Duloxetine - this interests me - as the binding profile is stronger for 5HT but, clinical observations suggest the effects on each transmitter is roughly equal.

Milnaciprane - not approved for depression but - one of the few agents that has dual action, but more selective for NE.
Any opinions on that?

Bupropion - remains an anomaly in my mind, but supposedly having DA actions as well as NE, perhaps meets the requisite for dual action, thus, less required NE receptor occupancy.
When I tried it before though, I experienced the immediate "buproprion honeymoon", then it faded - which would be consistent with cathinone tolerance.

And to hell with anything with mACh actions.
Cardiac implications of those are just too hard for me.


Opinions on them or alternate suggestions?

Duloxetine in particular - anyone tried it?

 

[musique]

Cymbalta ( Dualoxetine) is about 10:1 ~ Sero to NE, Effexor is 30:1 , Pristiq ( Desvenlafaxine) is 14:1, Milnaciprin(Savella) is 1.6:1[although I heard more consistent ratios of 1:3 from my other studies/sources] and Levomilnaciprin( Fetzima) -1:2

From the Tricyclics, the highest Noradrenergic synthesis is going to be from desipramine which is from my "Rough calculation" about 7:1 The cardiac adverse effects are not bad with this one.

Strattera which is more of a NRI used for ADD successfully in some individuals has a ratio of 15:1 However this is chiefly confined to the PFC as there is barely any binding affinity in the Striatum. This may be one of the factors which contributes to it's mechanism of action as opposed to a drug with an overall ( on paper) similar ratio such as Cymbalta.

Perhaps some other members can chime in re: the MAO class of Anti-D's

https://en.wikipedia.org/wiki/Levomilnacipran

 

[Cotcha Yankinov]

Stahls book brings up more than once that, in agents where there is a dual mechanism of action, the normally requisite 90% occupancy of NE receptors required for efficacy, may be significantly reduced - due to the dual mechanisms of action.

It seems that there are some mutually shared signaling cascades/effectors downstream of 5-HT and NE receptors - in this manner, there may be some cross-sensitization to the therapeutic response. Mind us, the same cell can express both 5-HT and NE receptors.

 

[jaiho]

Clomipramine is 2:1 NA/5HT ratio.
Most potent SNRI available unless you do a SSRI + NRI combo.

 

[JohnBoy2000]

Strattera which is more of a NRI used for ADD successfully in some individuals has a ratio of 15:1 However this is chiefly confined to the PFC as there is barely any binding affinity in the Striatum. This may be one of the factors which contributes to it's mechanism of action as opposed to a drug with an overall ( on paper) similar ratio such as Cymbalta.

I would have difficulty getting milnacipran I guess.
Not approved for MDD and, also not available in the UK.

Regarding strattera affected regions - exclusive to the PFC?
That's a new one on me.
I didn't think they had made drugs that could discriminate between brain regions.

Any paper links on that by chance?

 

[Ozle]

What sort of effects exactly are you looking for from these types of molecules?

 

[Cotcha Yankinov]

Regarding strattera affected regions - exclusive to the PFC?
That's a new one on me.
I didn't think they had made drugs that could discriminate between brain regions.

NRI's tend to have unique effects on the PFC because the dopamine reuptake there is handled largely by the NET. Increase catecholamines in the PFC may help increase executive function, to a point (see Yerkes-dodson law)

 

[JohnBoy2000]

What sort of effects exactly are you looking for from these types of molecules?

Energy!

 

[JohnBoy2000]

NRI's tend to have unique effects on the PFC because the dopamine reuptake there is handled largely by the NET. Increase catecholamines in the PFC may help increase executive function, to a point (see Yerkes-dodson law)

Something something cortical pyramidal neurons?

I think musique was perhaps referring to no dopaminergic binding in the striatum?

I've certainly never read anything on the sister compounds of reboxetine and strattera different in terms of the brain regions implicated?

Atomoxetine - mild NMDA blocker, mild mu opioid blocker, kappa agonist. Given it's side effect profile, I'm personally inferring its effects on NA are more profound. i.e. more insomnia, more appetite loss, more headaches - effects associated with more intense NE amplification.

The remaining properties seem to be consist for them both; though I'm very much open to correction.

 

[musique]

Something something cortical pyramidal neurons?

I think musique was perhaps referring to no dopaminergic binding in the striatum?

You are correct and sorry for the delay in posting. It(Straterra, not the horror clown movie lol) does not alter dopamine levels in the striatum or Nucleus accumbens. This could be useful for those facing problems like Anxiety, OCD, racing thoughts etc. Although I was under the impression that dopamine occupying the caudate nucleus could be good for motivation, attention and higher levels of attention and memory ( retrieval, aquisition and retention?)

Based on what I discussed with "Cotcha Yankinov" in a previous thread, all Anti-D's increase dopaminergic and noradrenergic firing in the PFC because whether the drug is chiefly a 5HT2C antagonist or agonist, partial agonist etc..this effect down regulates and the result is this increase of DA and Nor-epi in the PFC.

Here is my source and further reading for Atomoxetine( Strattera) ..... https://en.wikipedia.org/wiki/Atomoxetine


BTW Johnboy, Are you sure you can't obtain milnacipran in the UK? It's brand name is "Ixel" I believe.

 

[JohnBoy2000]

You could be right there actually.

Approved in 1996.
Excellent - another option at least.

I think in terms of a drug combining 5HT and NE, with strong favor shown to NE - that may be the best option.

 

[Ozle]

Energy!

Wouldn't you be better off with a stimulant then? Or do you not tolerate those very well?

 

[JohnBoy2000]

Wouldn't you be better off with a stimulant then? Or do you not tolerate those very well?

For whatever reason, stimulants - Ritalin - never really did anything for me.

I tried it up to 20 mg only but - tolerance develops with them also so they're not really a long term solution.

 

[Cotcha Yankinov]

Ozle's mention of stimulants could be construed as including releasing agents e.g. Amphetamine, however addiction liability and risk of side effects increases with that class of drugs particularly and the sustainability may not be very high for some people.