Chill pills: why there are no Serotonin 5HT1A selective agonists RCs?

[Cotcha Yankinov]

I thought it was 5HT1A autoreceptors activation that is responsible for the observed AD affect of 1a agonists? It wont be trivial though getting a drug to selectively activate post-synaptic receptors but not autoreceptors since they pretty much the same as far as the drug molecule is concerned. Once in the synapse, it would bind "equally" to both!! But what difference would it make though?? in terms of AD effect

It seems as though sensitization of the post-synaptic 5-HT1A response and desensitization of 5-HT1A autoreceptors is important for AD response. A "preferential" 5-HT1A autoreceptor antagonist (pindolol) may help speed along response to SSRIs in some cases but I don't believe it functions as an antidepressant in isolation (although its not a selective 5-HT1A antagonist).

There can be some preference for binding to autoreceptors vs. heteroreceptors - it seems that when a receptor is coupled to a G protein the ligand's affinity typically increases, and there are differences in autoreceptor vs. heteroceptors in terms of what receptor populations tend to be coupled to G proteins.

Between the differences in binding kinetics therein, and differences in signaling cascades between heteroreceptors and autoreceptors, I would hope there is some hope of developing heteroreceptor preferential 5-HT1A agonists. There is still the issue of full agonist's side effects, but maybe some partial agonists can still produce a decent therapeutic response while not being overly active at autoreceptors. I would assume that buspar's mechanism of action may actually involve chronic dosing desensitizing 5-HT1A autoreceptors and the partial agonism activating post synaptic 5-HT1A, rather than the benefits being downstream of decreased synaptic 5-HT.

 

[MeDieViL]

It seems as though sensitization of the post-synaptic 5-HT1A response and desensitization of 5-HT1A autoreceptors is important for AD response.

This is dependent on the type of depression, 5ht2a activation is involved in the therapeutic response to atypical depression while downregulation of that receptor is implicated in the response to melancholic depression.

 

[Scrofula]

The autoreceptors being desensitized (in that model of SSRI action) are neither pre- nor post-synaptic, they're on the cell bodies of serotonergic neurons in the raphe nuclei, that form those axonal projections.

 

[Coolwhip]

I believe there are a number of new serotonin modulating ADs; with 5HT1A agonist activity. Such as vortioxetine.

 

[DotChem]

This model of antidepressants MOA makes some senses with SSRI but not with 5HT1a direct agonists imho (or Serotonin releasers like MDMA). If I understand correctly, 5HT1a DRN autoreceptors basically function as sensors in a feedback loop to regulate released 5HT levels in synapse by inhibiting its further release and ending neuron firing. Serotonin transporter (SERT) on the other hand removes 5HT released within the synaptic cleft and transport it back to the neuron for storage (and reuse?) It saves energy compared to de nuovo synthesizing serotonin every time the neuron needs it to fire. So the 2 mechanisms of regulating serotonin levels (and the firing of serotonergic neurons) are working together to regulate serotoninergic firing.

Now, SSRIs prevents the reuptake of released 5HT which will have no effect as long long as the HT1a autoreceptors are in the basal state ie fully sensitized: 5HT levels will still be regulated via 1a autoreceptors feedback loop. Of course, chronic activation leading to desensitization of 1a autoreceptors would lead to "increase" (or at least persistent signaling) serotonin levels since you now have blockade of the 2 modes of regulating 5HT. That might explain the time lag of SSRI to work. Another way to achieve same effect is simply blockade of 1a autoreceptors which may explain the antidepressant effect of some 5HT1a antagonists like pindolol. Sure, if you were to block 1a autoreceptors AND inhbibit reuptake the neurotransmitter at the same time, you get more bang for your money (5HT reuptake inhbition + disinhibition of 5HT release).

Having said that, activation of 1a autoreceptors by direct agonists will lead to inhibition of further serotonin release (NOT THE AGONIST). The agonist is still available to bind and activate postsynaptic receptors and lead to AnxiolyticAD response that would have been coming from the endogenous serotonin binding to post-synaptic 5HTRs! So you'll have serotonergic response regardless of 5HT1a levels. At least the response mediated by the 5HT1a subpopulation of 5HTs. The challenge is that if you are dealing with a selective 1a agonist, you'll now have less serotonergic activation of the other 13 different or so 5HT subtypes (5HT1D/B, 5HT2, 5HT3, 5HT6..etc etc) because by activating autoreceptors, the agonist is decreasing overall serotonin available. It is as if direct 5HT1a autoreceptors agonists are also indirectly antagonist of other serotonergic subtypes (pretty complex!).

As I said, chemically ( as far as rational drug design concerned) it is incredibly difficult to come up with a molecule that is selective post-synaptic 5HT1A agonist: the drug molecule cannot differentiate between auto and heteroreceptors: it would bind (and activate both) without discriminating although with opioids as I mentioned above, activation by different agonists may lead to different downtream signaling like morphine compared to endorphins. Difficult but not impossibe, afaik nobody has yet come up with a rationale on what makes a molecule functionally slective: you'll just have to random screen millions of molecules(at ca $200/molecule that's lots of money!! way beyond my payscale as a homeless person working daylabor). Another approach is manipulating pharmacokinetic parameters of the drug molecule so that it selectively distributes to one or the other brain regions (difficult to predict a priori!!). As I mentioned, you can easily get molecules cross BBB and get in the brain but hard to tell them where to go once there!!
As for the anxiolytic effect of 5HT1a activation by agonists, it seems unrelated to the observed AD effect. Here is a recent review:

Association of 5-HT1A Receptors with Affective Disorders
By Cesar Soria-Fregozo, Maria Isabel Perez-Vega, Juan Francisco Rodríguez-Landa, León Jesús Germán-Ponciano, Rosa Isela García- Ríos and Armando Mora-Perez

Imho, the best anxiolytic/antidepressant 5HT1a agonist drug would be one that is also serotonin releaser (releaser not uptake inhibitor!). With SRAs (serotonin releasers like MDMA exctasy) autoreceptors activation would not be relevant since the level of released serotonin in the synaptic cleft would just be baseline ie autoreceptors activation by the agonist regulate 5HT level to baseline and activation of postsynaptic 5HTa brings about the intended anxiolytic/serenic/antidepressant effect without f...g up other 5HT receptors subtypes states... but who knows?

NB: actually one such drug I came across is mepiprazole (or its cousin tolpiprazole . It is an anxiolytic (minor tranquilizer) developed in the 70s in Germany and was (is?) used in Spain as anxiolytic to treat "neurosis" aka stressthe syout. It is a 5HT DA NE releaser (more selective for 5HT than DA/NE) and a 5HT1a agonist. I am not sure if it is still prescribed in Spain (if anybody please let me know). It was probably displaced with the introduction of benzodiazepines anxiolytics (t’was the craze with Valium & co back then right?). I would certainly bet this molecule would be the perfect “chill pill”. Unlike benzodiazepines and other GABAergic, activation of 5HT1a by anxiolytics (at least as seen with Buspar) does not lead to sedation, drowsiness, tolerance, withdrawal, is faster and safer than with benzos.. (cf this ref here)...The only issue is priapism aka the “exploding penis” (would look at that issue further if it is related to 5HT1a agonism per se or specifically with Buspar though)..

 

[DotChem]

There can be some preference for binding to autoreceptors vs. heteroreceptors - it seems that when a receptor is coupled to a G protein the ligand's affinity typically increases, and there are differences in autoreceptor vs. heteroceptors in terms of what receptor populations tend to be coupled to G proteins.
Between the differences in binding kinetics therein, and differences in signaling cascades between heteroreceptors and autoreceptors, I would hope there is some hope of developing heteroreceptor preferential 5-HT1A agonists.

That is possible if the GPCRs 1a autoreceptors and heteroreceptors couple to different downstream signalings pathways since desensitization of 1a receptors apparently does not involve down regulation of their transcription ie same receptor density before and after chronic activation. I don't know whether downstream effects affect ligand affinity: with opioid at least I don't think that is the case. Here is paper looking at what the relationship between ligand binding and selective downstream effects ( For 5HTRs agonist efficacy is unchanged upon chronic dosing afaik only the downstream response. Unlike opioids GPCRs which couple to G protein and/or beta arrestin following chronic activation, afaik 1a autoreceptors couple to G protein only (not sure though about current literature). So with 5HT GPCRs desensitization, something is happening downstream to G protein activation (down-downstream so to speak). Perhaps at the level of the potassium ion channels which the G protein activates following its own activation by agonists-5HT GPCR interactions. I mean intracellularly not extracellular like with ion channels such as nicotinic receptors where the channel is opened directly by agonist binding (from outside the cell)

 

[DotChem]

^ Sorry here is the link to ref: Identification of a Conformational Equilibrium That Determines the Efficacy and Functional Selectivity of the μ-Opioid Receptor
Dr. Junya Okude, Dr. Takumi Ueda, Dr. Yutaka Kofuku, Motohiko Sato, Naoyuki Nobuyama, Keita Kondo, Yutaro Shiraishi, Takuya Mizumura, Kento Onishi, Mei Natsume, Dr. Masahiro Maeda, Dr. Hideki Tsujishita, Dr. Takefumi Kuranaga, Prof. Dr. Masayuki Inoue, Prof. Dr. Ichio Shimada Angew Chem Int Ed Engl. 2015 Dec 21; 54(52): 15771–15776. Published online 2015 Nov 16. doi: 10.1002/anie.201508794

 

[Cotcha Yankinov]

afaik 1a autoreceptors couple to G protein only

Sorry I should've been clearer, what I mean to say is that some 5-HT1A receptors are not actively coupled to G-proteins. These uncoupled 5-HT1A are said to be in the "low affinity state" - agonists apparently have higher affinity for G-protein coupled e.g. 5-HT1A than a 5-HT1A receptor that isn't actively coupled.

The 5-HT1A coupled to G proteins are said to be in the "high affinity state", and I think some of the 5-HT1A ligands are said to have preference for somatodendritic/autoreceptor binding becacuse more of those receptors are in the high affinity state.

But you raise an interesting point about 5-HT1A agonism at autoreceptors not being a big deal in terms of decreasing post-synaptic 5-HT1A activation (that you could just raise the dose to compensate for decreased 5-HT release) but that it would be a problem for activation of other 5-HT subtypes. Makes me wonder if serotonin agonists hold some use... There could certainly be some subtypes to avoid, e.g. 5-HT3 agonism, but considering part of the delay in SSRI action has to do with the time it takes for autoreceptors to desensitize, serotonin agonists do bypass that problem.. Much like releasing agents.

This might seem like rampant polypharmacy but I suppose one thing you could do is figure out what 5-HT subtypes you wanted to agonize, then give individual selective ligands for each of the e.g. 10 5-HT subtypes that you want to activate, rather than finding one molecule that would do what you wanted at all 10 subtypes. Then if one subtype ligand seemed to give problems with insomnia (a common issue with SSRIs), a person could taper off that subtype's ligand before bedtime and resume it in the morning.. Or if one subtype gave problems with sex drive, one could taper it off a bit before a date, et cetera et cetera... Or go ultra polypharmacy and take an antagonist to counter the undesired effects

 

[Scrofula]

Again, there HAVE been heteroreceptor-selective 1a agonists developed, as well as somatodendritic autoreceptor-selective 1a agonists, that indeed cause different (rat) brain regions to activate, and lead to different behaviors.

If we take a non-discriminating selective 1a agonist, one that also targets somatodendritic autoreceptors, then you could imagine it, like Mr. Chem said, of functionally being an antagonist at all the other subtypes--like mirtazapine. An agonist selective for heteroreceptors (which, again, do exist), would lack that global effect. BUT, one of the models to drugs like mirtazapine's efficacy is antagonism (or inverse agonism) of HT2c and its downstream effects on DA and NE. Thus you might lose any anxiolytic effects with the heteroreceptor-selective drug (and the anti-addiction potential), and might explain why we don't see any on the market.

The problem with monoamine-releasing drugs is that they seem to get you too high to be an after-work refresher.

 

[DotChem]

Sorry I should've been clearer, what I mean to say is that some 5-HT1A receptors are not actively coupled to G-proteins. These uncoupled 5-HT1A are said to be in the "low affinity state" - agonists apparently have higher affinity for G-protein coupled e.g. 5-HT1A than a 5-HT1A receptor that isn't actively coupled.
The 5-HT1A coupled to G proteins are said to be in the "high affinity state", and I think some of the 5-HT1A ligands are said to have preference for somatodendritic/autoreceptor binding becacuse more of those receptors are in the high affinity state.

That makes senses: the differential binding of agonist to the high-affinity or low-affinity form of the GPCR: If that is the issue, then yes you should (at least in theory) be able to come up with molecules that selectivity target one or the other form of the same receptor. So if high-affinity form of 1a receptors mostly localize to somatodendrites then one should be able to selectivity target one or the other populations with a selective agonist (eg with morphinans and related opioids there are lots example..

Makes me wonder if serotonin agonists hold some use...

...Serotonin 5HT1A that are also 5HT Releasers much like MDMA or the phenylpiprazines I mentionned earlier. Think about it: postsynaptic 1A activation would in that case be as clean as it get. Autoreceptors activation of 5HT1a agonism would take care of 5HT levels and postsynaptic 1A activation leading to AD/anxiolytic/serenic/empathogen response witout affecting other serotonergic!! [/QUOTE]

This might seem like rampant polypharmacy.. Or go ultra polypharmacy and take an antagonist to counter the undesired effects

No need for polypharmacy really or to blockade autoreceptors activation: we already have drugs 5HT1a agonist that are also Serotonin Releasers(MDMA is one other less neurotoxic among phenylpiperazines...

 

[DotChem]

Again, there HAVE been heteroreceptor-selective 1a agonists developed, as well as somatodendritic autoreceptor-selective 1a agonists, that indeed cause different (rat) brain regions to activate, and lead to different behaviors.

would come back to that once having chance to go through some lit on that...

The problem with monoamine-releasing drugs is that they seem to get you too high to be an after-work refresher.

Much of monoamines-releasing drugs are not selective for 5HT. To some extent there'll also trigger release of DA and NE and so you would have more than the antidepressant/anxiolytic/serenic effect of 5HT1a activation. Amphetamines MA releasers (like MDMA) are also DA/NE releasers (SNDRAs) so you'll get the “high” of increased DA and NE neurotransmision in addition to the antidepressant/anxiolytic/serenic effect of increased 5HT1a neurotransmission. One exception though among the amphetamines are the amino indene type amphetamines (discovered by Nichols). For example MDAI 3,4-(methylenedioxy)-2-aminoindene (MDAI) is reportedly selective serotonin releaser. It doesnt give you stim high/arousal It is actually being claimed as a potential fast acting antidepressant with no stim effect (check out the wiki). I don't know if it is also 5HT1a agonist like its cousin, MDMA (would probably email Professor Nichols to check this out..without bothering the old psychedelic chemist in his peaceful retirement .

Likewise, DMT and several other tryptamines are also SNDRAs in addition to being 5HT1a agonists. Maybe some are more selective SRAs than others, I don't know. As suggested by @Limpet_Chicken, the after-glow of DMT may be due simply to 5HT1a activation. And of course the psychedelic effect due to 2A/C agonism. Which you don't necessarily want if you're after a pure serenic experience.

Again, the best I come across in the literature for this purpose (anxiolytic/serenic/empathogen without stim arousal or 2a psychedelia) are the phenylpiperazines like mepiprazole a drug used (was used?) in spain as anxiolytic. It is selective 5HT releaser and 5HT1a agonist. Here some papers on this drug:

Placheta P, Singer E, Kriwanek W, Hertting G (August 1976). "Mepiprazole, a new psychotropic drug: effects on uptake and retention of monoamines in rat brain synaptosomes". Psychopharmacology. 48 (3): 295–301. PMID 9660. doi:10.1007/BF00496865

(I know, pretty old study but as I said those drugs were not pursued as anxiolytics/antidepressant back then probably due to competition with the introduction of valium and the benzodiazepines around that time!.. but who knows?

 

[Cotcha Yankinov]

BUT, one of the models to drugs like mirtazapine's efficacy is antagonism (or inverse agonism) of HT2c and its downstream effects on DA and NE. Thus you might lose any anxiolytic effects with the heteroreceptor-selective drug (and the anti-addiction potential), and might explain why we don't see any on the market.

By extension, does buspar have some component of decreasing 5-HT2C activation via autoreceptor activation?

 

[Scrofula]

Buspirone I'd forgotten about till after I'd written all that argle bargle. But it seems to strongly activate autoreceptors (where specifically IDK), such that you see a decrease in serotonin in rat brains. That suggests lower activation of HT2c, not quite the same as inverse agonism, but maybe meaningful. Problem with a lot of these HT1a agonists is they also agonize dopamine receptors and adrenergic receptors. It makes it pretty difficult to tease apart which effects are due to what chemistry.

I'll have to dig up anything on buspirone's HT2c effects. How do you even measure that with everything else going on?

 

[motiv311]

Maybe Tianeptine is sort of like this?

 

[Scrofula]

No, tianeptine actually ignores all these systems completely, and targets the mu opioid receptor instead. Which is pretty strange to me, since that usually gets you high. Or do you mean, if the quest is for an after-work mood-booster/stress-reliever, why not something like that? I just can't imagine how a low-dose opiate wouldn't quickly turn into lots of low-dose opiates and then suddenly heroin.

 

[Cotcha Yankinov]

I remember reading about Mirtazapine's inverse agonism at 5-HT2C and that it seemed to produce categorically different effects on the midbrain than a 5-HT2C silent antagonist they were using.

Is this a situation where beta-arrestin signaling activates MAPK to produce some cellular change that may not be realized with a normal rate of downregulation due to natural agonism? I suppose my question really is, is downregulation of 5-HT2C with chronic agonism (a la SSRIs) categorically different than inverse agonism?

 

[Scrofula]

Couldn't tell you about the signalling pathways. I don't know how an SSRI would produce chronic agonism of HT2c, either, unless you think elevated serotonin would do that.

I can see though, how an inverse agonist would be categorically different than a reduction in natural ligand, like what would occur with serotonin if an HT1a agonist alone was used. One is just a reduction in signal, the other is an "active" blockade of the signal. But yeah, I don't know how that gets translated within the cell, or even what "active" means there, much less how it affects DA and NE transmission. I say I can "see" it, but as bouncy balls in my head, not actual understanding.

 

[Volsam]

Interestingly enough, a lot of the antidepressant 5HT1A agonists are also Sigma-1 agonists, this one looks pretty nice: https://en.wikipedia.org/wiki/Eltoprazine

 

[Scrofula]

What I find interesting about sigma1 agonism is its purported benefit in dementia. Mainly because i've been on sertraline, a sigma1 antagonist, for too long. Has it made me dumber? Will it make future treatment with an agonist twice as effective? If sigma1 plays a role in dementia, what are the effects of taking agonists or antagonists long-term in your early retirement years? Or really, any time.

 

[Volsam]

What I find interesting about sigma1 agonism is its purported benefit in dementia. Mainly because i've been on sertraline, a sigma1 antagonist, for too long. Has it made me dumber? Will it make future treatment with an agonist twice as effective? If sigma1 plays a role in dementia, what are the effects of taking agonists or antagonists long-term in your early retirement years? Or really, any time.

Wondering that myself...

My gut tells me I would always prefer sigma agonists and they do make me feel a lot better. But I think that individual chemistry differences and personal metabolism are what is of the most importance.
Surely there's a lot more work needs to be done in the direction of understanding functions of 5HT1A and Sigma receptors.