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Relative Selectivity of A/Ds for Serotonin Over NA and DA Uptake

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Dope_User

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http://www.australianprescriber.com/magazines/vol22no5/experimental1.htm

Table 1 shows the "Relative selectivity of new antidepressants for serotonin over noradrenaline and dopamine uptake." What I'm looking for is the same values for "Selectivity 5HT vs. noradrenaline" and "Selectivity 5HT vs. dopamine" for Cymbalta (duloxetine).

Anyone know where I can find this? Actually, if you know where I could find a "full" list of these, such as for all, or most, SSRIs, newer/atypical A/Ds - Wellbutrin, Remeron, tricyclics, that would be greatly appreciated. Thanks.
 
A full list you're not going to find, you could do a pubmed search for drugs of interest, this image is quite comprehensive, but only has SERT vs NET
51144Antidepressants_affinities.gif


This one has SERT NET and DAT but doesn't have as many
51144Rothman_Affinities.gif


Still, hope that helps.
 
Dope,

This is an interesting article. I wonder if anybody has explored a theory of serotonin release by MDMA potentially being 5HT1a antagonist.
 
Um, serotonin, in a general sense, couldn't really be a 5-HT1A antagonist, as it is a 5-HT1A agonist.

Fast: not off the top of my desktop, I've got a brief mention in Battaglia G, De Souza EB. Pharmacologic profile of amphetamine derivatives at various brain recognition sites: selective effects on serotonergic systems. NIDA Res Monogr. 1989;94:240-58. that MDA is 1.8 times as potent at blocking 5-HT uptake as MDMA, while MDE 0.4... but no nice, Rothman synaptosomes stuff.
 
_Um, serotonin, in a general sense, couldn't really be a 5-HT1A antagonist, as it is a 5-HT1A agonist.
Click to expand...

Is serotonin an agonist for a 5HT receptor? I understood that 5HT receptors were serotonin receptors. I also thought a number of drugs were both serotonin antagonists AND agonists, just at different receptor sites.
 
Less see, yes, serotonin is an agonist at 5-HT receptors.
5-HT receptors are serotonin receptors... 5-HT = serotonin
A drugs could be an agonist at one serotonin receptor while an antagonist at another serotonin receptor, though I can't think of any.
 
What I cant understand is that if amitriptyline is a potent NET uptake inhibitor, why it makes me drowsy and want to go to sleep.
 
MDMA isn't a 5-HT1A antagonist, because it has no affinity for the 5-HT1A receptor.

The serotonin it releases isn't a 5-HT1A antagonist, because serotonin is a 5-HT1A agonist.

Amitrip is a very high potency antihistamine, that's why it makes you sleepy.
 
From www.RxList.com
Amitriptyline HCl is an antidepressant with sedative effects. Its mechanism of action in man is not known. It is not a monoamine oxidase inhibitor and it does not act primarily by stimulation of the central nervous system.
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It states that amitriptyline is an antidepressant with sedative effects and does NOT work primarily by stimulation of the CNS, although it indirectly inhibits of reuptake of norepinephrine and serotonin. As with many antidepressants restlessness, excitement, and insomina are listed as side effects, but so are weakness, drowsiness, and fatigue...just shows that all medications can affect people different and this seems to prove especially true with antidepressants.

One thing I'm quite interested in is a comparison and contrast between the "older" tricyclic A/D's and the "newer" SSRIs, mainly in terms of efficacy, but in terms of pharmacological actions as well (as best as is known, especially concerning effect on various neurotransmitters believe to play a role in depression, mainly serotonin, norepinephrine, and dopamine).

On a side note, and unrelated, what is epinephrine and how does it different from norepinephrine, is any and all aspects? Oh, and what was that antidepressant that could cause spontaneous orgams and I believe was either banned or never approved for use in the US? Is it still available elsewhere? And wasn't there a company develop a similar, "newer version," or that drug (in France maybe)? Any information on the "spontaneous orgasm" A/D as well as the similar, newer A/D would be greatly appreciated. I, once again, am trying to learn as much as possible about antidepressants, mainly SSRIs, SNRIs, SSNRIs, SDRIs, and the tricyclics (don't care about MAOIs). Alist of SNRIs, SSNRIs, and SDRIs would be appreciated...sorry for the massive amount of questions/requested information all in one post, but it is my thread! :D
 
Nearly all SSRI's cause drowsyness because they are lacking in their ability to inhibit NET uptake. Citalopram is very very good at producing narcolepsy type symptoms IMO.

What I was forgetting wrt Amitryp. is that histamine is an important brain chemical in controlling wakefullness the opposite side of the coin of which is melatonin producing 'sleepfullness'.

That is why I thought alphamethyl-histamine might be ok instead of pro-plus pills. I guess industry is probably looking for something to do with the by-product from all their decaffinated bevervages.
 
The spontaneous orgasm antidepressant is amineptine; it's primarily a dopamine reuptake inhibitor (which probably goes towards why it has an abuse potential).

As regards older tricyclic antidepressants, about the only thing they do have in common is that they inhibit noradrenaline reuptake, although ones like anafranil also have an effect on the reuptake of serotonin (there are some others with a bit of a different profile, like protryptaline that has stimulant properties)

That is why I thought alphamethyl-histamine might be ok instead of pro-plus pills

Adding an alpha-methyl group to a histamine molecule will most probably give a histamine like agonist that is resistant to metabolic attack; given that systemic doses of histamine will cause a huge drop in blood pressure due to histamines actions as a vasodilator, and making the walls if the blood vesseld "leaky", alpha-methylhistamine will most likely produce a long lasting, but less severe version of anaphylaxis - not good in anybody's book.


Lastly, adrenaline is noradrenaline with a N-methyl group (adrenaline being 1-(3,4-dihydroxyphenyl)-2-methylaminoethanol). Adrenaline is more active at beta-adrenoreceptors whereas noradrenaline is mainly active at alpha-adrenoreceptors
 
Nearly all SSRI's cause drowsyness because they are lacking in their ability to inhibit NET uptake. Citalopram is very very good at producing narcolepsy type symptoms IMO.
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I beg to differ. Nearly every SSRI I've ever taken has caused insomnia. The insomnia with Paxil was the absolute worst. I had difficulty falling asleep, frequent wakenings, and once I woke up around 5 or 6 AM I was up for the day (and I normally get up at noon). I was on it for about 2 weeks (hoping this side effect would fade) but it never did. I would go 3 days and sleep a total of maybe 10 hours while I normally sleep 10 hours a night. Around day 4 or 5, I'd probably get about 5-6 hours that night due to extreme exhaustion. Citalopram? I can't remember if that's Celexa or Lexapro (I think Celexa but I don't feel like looking it up). Any way, both of those had the least effect on my sleep...I was told they were newer and even more "selective" than most SSRIs - like SSSRIs (first S for Super, my term). I attributed the fewer side effects of these two A/Ds due to this higher selectivity.
The spontaneous orgasm antidepressant is amineptine; it's primarily a dopamine reuptake inhibitor (which probably goes towards why it has an abuse potential).
Click to expand...
I have heard about the abuse potential although I can't imagine it's all that great of a high (in comparision to the commonly used illegal drugs). It's interest that it's primarily a dopamine reuptake inhibitor as is Wellbutrin. But the latter does not seem to have abuse potential. Maybe it would if higher doses (600+ instant relase at once) could be taken? But you'd be nuts to try that with the incredibly high risk of seizures from taking all that at once in the instant release formulation.
As regards older tricyclic antidepressants, about the only thing they do have in common is that they inhibit noradrenaline reuptake, although ones like anafranil also have an effect on the reuptake of serotonin (there are some others with a bit of a different profile, like protryptaline that has stimulant properties)
Click to expand...
I was under the impression that the TCAs work on serotonin, norepinephrine, and/or dopamine - depending on which TCA you are referring to. Although (in general), the TCAs seem to have more side effects than SSRIs, they seem to be at least as effective (if not more). I always attributed this to the fact that they work on more than just serotonin. I'm wondering if some of the newer (Cymbalta, to a lesser extent Effexor) and future antidepressants will be SSNDRIs (Selective Serotonin, Norepinephrine, and Dopamine Reuptake Inhibitors). Since dual uptake inhibitors seem to be gaining popularity (SERT and NE) and Wellbutrin effects dopamine (and is "somewhat" new or at least and "atypical" A/D), it's my guess that they take this to the next step and make an A/D that inhibits reuptake of all three. In fact, I found such an antidepressant that was in Phase II trials, IIRC. I'll try to find some information on that and get back to you.

What I'm still wondering about is my quotation about Remeron. Does it really cause the release of more serotonin and norepinephrine, or is a reuptake inhibitor of both, or does it cause release and reuptake inhibition of both? Assuming it causes the release of SERT and NE, what would effect would affects/result from combining Remeron and Cymbalta (an A/D that releases SERT and NE + an A/D that inhibits reuptake of both)? Possible serotonin syndrome? Or maybe norepinephrine syndrome (if such a thing exists)? If norepinephrine syndrome exists, what would be the symptoms/effects of that?
 
Following information is from the site http://www.neurotransmitter.net/newdrugs.html

I'm a fool...I had the "Future Treatments for Depression, Anxiety, Sleep Disorders, and Psychosis" bookmarked!
It has A/Ds (and other mental illness meds) in all stages of development/trials. Different ones have so many different mechanisms of actions, a lot much beyond/different from the the typical ones that act as serotonin, norepinephrine, and/or dopamine reuptake inhibitors. I mentioned that I saw a SSNDRI and there are a few: DOV 21, 947 (from DOV/Merck), GW372475, NS2359 (from GSK/NeuroSearch), SEP-225289 (from Sepracor), and DOV 102,677 (from DOV)...so it does seem as though (my self-titled) "SSNDRIs" are possible A/Ds of the future.

But like I said, many of these have unique mechanisms of action such as:
1. MAO-B inhibitor/weak MAO-A inhibitor [at higher doses]
2. beta-3-adrenoceptor agonist
3. NMDA antagonist
4. Voltage-gated sodium channel inhibitor, potassium channel activator
5. NK1 antagonist
6. NK2 antagonist
7. "Purified" Omega-3 [EPA] (Miraxion (formerly known as LAX-101) from Amarin for treatment of Depression and Huntington's Disease)***
8. GR antagonist
9. 5-HT1A agonist, sigma receptor agonist [also a serotonin reuptake inhibitor at higher doses]
10. Phenylalanine derivative
11. 5-HT1B antagonist
12. 5-HT1B and 5-HT1D receptor antagonist
13. 5-HT1A partial agonist
14. 5-HT1A partial agonist, serotonin reuptake inhibitor
15. 5-HT1A agonist, sigma receptor agonist (similar to 9)
16. mGluR2, mGluR3 agonist
17. GPCR modulator
18. V1B antagonist
19. 5-HT2C inverse agonist
20. PDE4 inhibitor
21. CRF1 antagonist
22. PDE4 inhibitor
23. FAAH (fatty acid amide hydrolase) inhibitor

That's over 20 new (at least new to me) possible ways at treating depression. If anyone knows anything about these mechanisms of action and how they would relate to depression, more specific how they'd help with depressive symptoms, please post. Also, which of these do you believe to be the most promising or the most potential and why?

***What's the difference between 7 and OTC Omega 3 fatty acid supplements from GNC (or even Wal*Mart)? Could I try taking Omega 3 supplements to help with my depression (after consulting my psychiatrist, of course)? Anyone have information/links about Omega 3 fatty acids and depression.
 
I was under the impression that the TCAs work on serotonin, norepinephrine, and/or dopamine - depending on which TCA you are referring to

Yes, but their main effects (except for the few exceptions like amineptine and anafranil) seem to be due to inhibition of reuptake of noradrenaline, the degree to which they exert reuptake inhibition of serotonin and dopamine being what gives the variety of different tricyclics.

PS. One you forgot to mention; kappa opiate receptor agonists. There a paper on erowid about salvia having an antidepressant effect - no doubt at least one of the pharmaceutical companies will be looking at how to divorce the antidepressant effect from the hallucinogenic effect
 
alpha-methylhistamine is the classical H3 receptor agonist... I've got a fucking truck load of it in my lab... It causes sleep as far as I'm awear.
 
tricyclics also cause b-adreno receptor down regulation. This would make one drowsy as well. Efexor does not have a great anti histamine effect nor great anti cholineric effect, but it does not cause increased energy in the long term (eventhough it inhibits ne and da reuptake). Efexor also has the same effect on beta adreno receptors (down regulation).
 
I know that effexor inhibits NET uptake as a functional part of its SAR. However i thought it had little if any effect on the DAT receptor, although it was never designed as an SSRI. Effexor was found to be an antidepressant purely by chance. Initially they had anticipated that it could stimulate opiate receptors, but then continued pursuing the project after this was shown to be 'not the case'.
 
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tricyclics also cause b-adreno receptor down regulation. This would make one drowsy as well.
Click to expand...

First, what exactly is b-adreno receptor down regulation? Well, actually I know what down regulation is, so really, what is the b-adreno receptor? smartshop, are you saying this is the MAIN reason that tricyclics cause sedation? What is the (or some of the) most sedative TCA(s), specifically ones that are often Rx'd for insomnia (in addition to depression)?

I'm most likely going to end up using a benzo (hoping to try temazepam next) for sleep, but I want to know some options that I haven't tried (and I've tried almost ALL of them). I'm thinking about trying 15 mg Remeron or maybe a sedating TCA (if you guys can suggest a good one)...15 mg of Remeron KNOCKED ME OUT in the past. I currently take 60 mg/day Cymbalta and 300 mg/day Lamictal (probably going up to 400 mg/day Lamictal). I wonder if my psychiatrist would be willing to Rx another A/D in addition to the Cymbalta b/c he has expressed significant concern over prescribing too much of an A/D (or A/Ds) due to the possibility of causing hypomanic or manic episodes (considering I'm bipolar). I am still a little depressed, so if I could add a low dose of Remeron or a sedating TCA, and it worked for my insomnia w/o day time drowsiness, maybe I could get that tiny bit of extra A/D effect that I'm looking for. How's this plan sound? My appointment is tomorrow, so replies by tonight (midnight is my bed time) would be greatly appreciated.
 
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