8-oh-dpat

[WSH]

According to wiki is has antidepressant,[7] anxiolytic,[8] serenic,[9] anorectic,[10] antiemetic,[11] hypothermic,[12] hypotensive,[13] bradycardic,[13] hyperventilative,[14][15][16] and analgesic effects[17]!

Why don't they use it?

 

[serotonin2A]

There are a multitude of reasons.

First, there is absolutely no evidence that DPAT has therapeutic effects in humans. It might, but it has never been administered to humans in a clinical trial. There are literally thousands of other 5-HT1A full agonists that produce the same effects as DPAT in animal models, and there is no real reason to favor DPAT over all the others.

DPAT was developed as a selective 5-HT1A agonist, but it is now known to bind to a variety of other 5-HT sites. The lack of selectivity means that DPAT is more likely to produce side-effects compared to agonists that are selective for 5-HT1A receptors.

Full 5-HT1A agonists tend to make people feel dizzy.

Even if DPAT had been found to be an effective therapeutic in humans, that doesn't mean that it would necessarily ever be used in humans. To be approved for human use, new drugs have to be (relatively) safe and effective, and they have to have some advantage over existing therapeutics. There isn't any reason to think that DPAT would necessarily clear that last bar.

 

[WSH]

what's your opinion on F-15,599?

It displays functional selectivity (also known as "biased agonism") by strongly activating 5-HT1A receptors in the postsynaptic prefrontal cortex while having little effect on somatodendritic autoreceptors in the raphe nucleus.[1][2] As a result, it has been touted as a preferential postsynaptic 5-HT1A receptor agonist and has been investigated as a novel potential antidepressant.[1][2][3]

PS: Could you please respond to this thread

The post where Montigny+Blier challenged your 8-oh-dpat receptor reserve theory.

I can also create a new thread if you want me to.

 

[serotonin2A]

what's your opinion on F-15,599?






PS: Could you please respond to this thread

The post where Montigny+Blier challenged your 8-oh-dpat receptor reserve theory.

I can also create a new thread if you want me to.

There are two seperate issues here. There are known G protein coupling differences between presynaptic and postsynaptic 5-HT1A receptors. The existance of a large reserve of presynaptic 5-HT1A receptors, and a relatively small reserve in hippocampus, has been confirmed by subsequent studies (see below for a few citations).

https://www.ncbi.nlm.nih.gov/pubmed/9652362

https://www.ncbi.nlm.nih.gov/pubmed/8248853

https://www.ncbi.nlm.nih.gov/pubmed/9328615

BTW, someone else in that thread tried to differentiate between 5-HT1A receptor effects on adenylate cyclase and GIRKs, but those two effectors are actually part of the same cascade. Galpha is coupled to adenylate cyclase, and Gbeta/gamma are coupled to GIRK channels.

It appears that F-15,599 is functionally selective. I'm not sure what specifically you were asking about in relation to that compound? The existance of such a compound doesn't really address the issues discussed in the other thread, because the action of F-15,599 isn't incompatible with the existance of a presynaptic receptor reserve. It is possible that there isn't a presynaptic receptor reserve for the effectors that F-15,599 activates, but there is one for DPAT and other agonists.

 

[WSH]

There are two seperate issues here. There are known G protein coupling differences between presynaptic and postsynaptic 5-HT1A receptors. The existance of a large reserve of presynaptic 5-HT1A receptors, and a relatively small reserve in hippocampus, has been confirmed by subsequent studies (see below for a few citations).

Yes, but this smaller reserve in the hippocampus can not be used to explain the partial agonist character of 8-oh-dpat:

The possibility that this apparent partial agonistic property in dorsal hippocampus might have been due to a low receptor reserve in this region can be ruled out on the following grounds: in our previous experiments (using the same paradigm as for R- and S-enantiomers), we have shown that even when a marked suppression of firing activity of the same neurons is obtained with microiontophoretic application of 5-HT itself, following the restoration of their firing with acetylcholine, then raising the application current of 5-HT was still able to produce a potent inhibition (Godbout et al 1991). This finding thus shows that the blockade of the effect of 5-HT by R-(+)-OH-DPAT and S-(-)-OH-DPAT cannot be ascribed to the activation of a maximal number of 5-HT1A receptors by the latter drugs. This finding also suggests that there are spare receptors in the CA3 region with respect to inhibition of firing.

 

[serotonin2A]

Yes, but this smaller reserve in the hippocampus can not be used to explain the partial agonist character of 8-oh-dpat:

The experiment reported in Godbout et al (1991) did not really address the receptor reserve hypothesis, and certainly wasn't designed to conclusively test the hypothesis. The discussion section that you quoted (from their 1996 paper on DPAT enantiomers) seems to be referring to Fig 7A in Godbout et al., which showed that "a background microintophoretic application of 5-HT did not reduce its own effectiveness".

What the experiment in Fig 7A showed is that 5-HT can produce inhibition of CA3 firing at concentrations that do not saturate receptors, meaning that it is possible to increase the effect by increasing the concentration of 5-HT. But all that shows is that the effect of 5-HT in CA3 is dose-dependent, and that 5-HT produces significant inhibition in CA3 even when applied at relatively low current intensities. In any event, either with single or dual iontophoretic application of 5-HT, the effect was apparently submaximal (they should have been able to produce greater levels of inhibition if they had applied higher currents), so the experiment wasn't really performed in a manner that would test whether there was a receptor reserve.

There are other problems with this type of experiment that make interpretation difficult. Electrophysiology studies focusing on one receptor usually avoid using 5-HT because it is non-selective. There are other 5-HT receptor subtypes besides 5-HT1A that could mediate the observed inhibition. The design of the experiment isn't unreasonable given the aims of the 1991 study, but it is far from optimal for testing the receptor reserve hypothesis.

 

[WSH]

The experiment reported in Godbout et al (1991) did not really address the receptor reserve hypothesis, and certainly wasn't designed to conclusively test the hypothesis. The discussion section that you quoted (from their 1996 paper on DPAT enantiomers) seems to be referring to Fig 7A in Godbout et al., which showed that "a background microintophoretic application of 5-HT did not reduce its own effectiveness".

What the experiment in Fig 7A showed is that 5-HT can produce inhibition of CA3 firing at concentrations that do not saturate receptors, meaning that it is possible to increase the effect by increasing the concentration of 5-HT. But all that shows is that the effect of 5-HT in CA3 is dose-dependent, and that 5-HT produces significant inhibition in CA3 even when applied at relatively low current intensities. In any event, either with single or dual iontophoretic application of 5-HT, the effect was apparently submaximal (they should have been able to produce greater levels of inhibition if they had applied higher currents), so the experiment wasn't really performed in a manner that would test whether there was a receptor reserve.

There are other problems with this type of experiment that make interpretation difficult. Electrophysiology studies focusing on one receptor usually avoid using 5-HT because it is non-selective. There are other 5-HT receptor subtypes besides 5-HT1A that could mediate the observed inhibition. The design of the experiment isn't unreasonable given the aims of the 1991 study, but it is far from optimal for testing the receptor reserve hypothesis.

OK, let's agree to disagree on the receptor reserve

lets talk about F15599:

it totally reduced immobility in the forced swimming (ssri only do it partially)

do you think it works in humans?


PS: i sent you a friend request, it's ok if don't accept

 

[serotonin2A]

OK, let's agree to disagree on the receptor reserve

lets talk about F15599:

it totally reduced immobility in the forced swimming (ssri only do it partially)

do you think it works in humans?


PS: i sent you a friend request, it's ok if don't accept

The FST results are interesting but I would hold off on getting too excited. It is certainly true that antidepressants reduce immobility in the FST, but I don't think that any novel FST screening "hits" have ever made it all the way to the clinic (ie, the FST is probably not a great way to screen new antidepressants -- ie, the mice are not actually depressed). I'm as guilty as other investigators because I have used the FST to test new compounds, but it is important to keep its limitations in mind.

So I don't really know if it would work in humans. Even if it is effective, it might night be a good drug candidate.

I wonder if it would work as an adjunct antipsychotic or an anxiolytic?

 

[Cotcha Yankinov]

I'm a bit confused on the matter of 5-HT1A ligands having selective occupancy for somatodendritic vs. heteroceptors. For example "- we previously demonstrated a preferential occupancy of 5-HT_1A autoreceptors, compared to postsynaptic receptors by pindolol in healthy volunteers." (http://www.nature.com/npp/journal/v29/n9/full/1300472a.html)

Are they implying that pindolol actually has different affinity for somatodendritic vs. heteroceptors? What would give rise to this phenomenon? Are there PK factors at work that result in more accumulation of the drug near cell bodies/dendrites, or differences in how the receptors are actually sitting on the different cells in different locations but no difference in the gene that actually produces the 5-HT1A receptor itself?

Does the G-protein coupling of ie 5-HT1A affect the affinity of ligands?

 

[serotonin2A]

I'm a bit confused on the matter of 5-HT1A ligands having selective occupancy for somatodendritic vs. heteroceptors. For example "- we previously demonstrated a preferential occupancy of 5-HT_1A autoreceptors, compared to postsynaptic receptors by pindolol in healthy volunteers." (http://www.nature.com/npp/journal/v29/n9/full/1300472a.html)

Are they implying that pindolol actually has different affinity for somatodendritic vs. heteroceptors? What would give rise to this phenomenon? Are there PK factors at work that result in more accumulation of the drug near cell bodies/dendrites, or differences in how the receptors are actually sitting on the different cells in different locations but no difference in the gene that actually produces the 5-HT1A receptor itself?

Does the G-protein coupling of ie 5-HT1A affect the affinity of ligands?

Agonists have higher affinity for receptors that are coupled to G proteins compared to uncoupled receptors. The proportion of 5-HT1A receptors that are G protein coupled is reportedly highest in presynaptic regions, meaning that a large proportion of 5-HT1A receptors in presynaptic regions will be in the agonist high affinity state.

 

[WSH]

The FST results are interesting but I would hold off on getting too excited. It is certainly true that antidepressants reduce immobility in the FST, but I don't think that any novel FST screening "hits" have ever made it all the way to the clinic (ie, the FST is probably not a great way to screen new antidepressants -- ie, the mice are not actually depressed). I'm as guilty as other investigators because I have used the FST to test new compounds, but it is important to keep its limitations in mind.

So I don't really know if it would work in humans. Even if it is effective, it might night be a good drug candidate.

I wonder if it would work as an adjunct antipsychotic or an anxiolytic?

Moving on to befiradol (F-13640):

It has powerful analgesic and antiallodynic effects comparable to those of high doses of opioid painkillers, but with fewer and less prominent side effects, as well as little or no development of tolerance with repeated use.[1][2][3][4][5]

Do you think in the (far) future (i know clinical trials last many years, sometimes up to ten!) that it would replace morphine, especially because befiradol causes no tolerance?

 

[serotonin2A]

Moving on to befiradol (F-13640):

Do you think in the (far) future (i know clinical trials last many years, sometimes up to ten!) that it would replace morphine, especially because befiradol causes no tolerance?

There are several reasons why befiradol could not serve as a general replacement for morphine. Acute administration produces some degree of hyperalgesia. Its also not clear from the studies you posted that befiradol is actually effective against acute pain (notice that they didn't test it in the tail flick or hot plate assays). They used the formalin test, which is a model of persistant pain.

Befiradol might be a useful drug for chronic pain. However, as a caveat, if you take a look at Bardin et al 2003 (http://www.karger.com/Article/Pdf/68404) you will notice that U-50488 is also very effective in their model. Just because a drug is efficacious doesn't mean that it is actually useful. Just like U-50488, befiradol may be an effective analgesic, but that doesn't mean that any patients would be willing to take it more than once.

 

[Cotcha Yankinov]

Agonists have higher affinity for receptors that are coupled to G proteins compared to uncoupled receptors. The proportion of 5-HT1A receptors that are G protein coupled is reportedly highest in presynaptic regions, meaning thata large proportion of 5-HT1A receptors in presynaptic regions will be in the agonist high affinity state.

Does much of what is known about D2 high affinity state induction with amphetamine/psychosis apply to 5-HT1A? For example, might more 5-HT1A high affinity states or heterodimer complexes form with increasing 5-HT signaling? Might depressed patients be expected to have altered ratios of low - high affinity state 5-HT1A in the same sense that people with psychosis may have altered ratios of low - high D2 states? Although I seem to be reading about some disagreement that high affinity D2 states are noted in schizophrenics (https://www.ncbi.nlm.nih.gov/pubmed/18987627)

The matter of D2-like/A2A receptor complexes seems a bit different although the studies are very recent (https://www.ncbi.nlm.nih.gov/pubmed/26987369 - "Cocaine self-administration differentially affects allosteric A2A-D2 receptor-receptor interactions in the striatum. Relevance for cocaine use disorder"

"The results therefore support the hypothesis that A2AR agonists can at least in part counteract the motivational actions of cocaine. This action is mediated via the D2-likeR by targeting the A2AR protomer of A2AR-D2-like R heteroreceptor complexes in the ventral striatum, which leads to the reduction of D2-likeR protomer recognition through the allosteric receptor-receptor interaction."

https://www.ncbi.nlm.nih.gov/pubmed/27984074 - "The selective reappearance of antagonistic A2AR-D2R receptor-receptor interactions in the ventral striatum after amphetamine challenge in the amphetamine sensitized rat may give one possible mechanism for the atypical antipsychotic-like actions of A2AR receptor agonists"

Hearing about all these interactions with D2 - A2A and D2 - 5-HT2A, I wonder if there is anything special going on with 5-HT1A heterodimers in depressives or with SSRI/SRA response.

For example https://www.ncbi.nlm.nih.gov/pubmed/26995955 - "5-HT7 receptor appears to be a modulator for 5-HT1A receptor - the key autoregulator of the brain serotonin system; iii) 5-HT1A/5-HT7 receptor complexes formation is one of the mechanisms for inactivation and desensitization of the 5-HTIA receptors in the brain; iv) differences in the 5-HT7 receptor and 5-HTIA/5-HT7 heterodimers density define different sensitivity of pre- and postsynaptic 5-HTlA receptors to chronic treatment with selective serotonin reuptake inhibitors."

https://www.ncbi.nlm.nih.gov/pubmed/25642174 - "Selective pharmacological blockade of the 5-HT7 receptor attenuates light and 8-OH-DPAT induced phase shifts of mouse circadian wheel running activity."

Seems like 8-OH-DPAT really does have the issue of not being selective for 5-HT1A. And if it has decent affinity for 5-HT1A and whatever affinity for 5-HT7, and 5-HT1A/5-HT7 form heterodimers, it seems like there could be even more complication of results there.


Edit: I forgot to ask my actual question.

May an uncoupled ie 5-HT1A receptor dimerize with a coupled receptor, and then may a ligand binding to the (formerly) uncoupled 5-HT1A receptor actually have functional effects?

 

[WSH]

Agonists have higher affinity for receptors that are coupled to G proteins compared to uncoupled receptors. The proportion of 5-HT1A receptors that are G protein coupled is reportedly highest in presynaptic regions, meaning that a large proportion of 5-HT1A receptors in presynaptic regions will be in the agonist high affinity state.

yes, you're right, although the density is higher in the frontal cortex (and especially in the hippocampus [in the CA3 and such]) the proportion of the high affinity states is definitely higher in the raphe dorsalis, making direct 5-ht1a agonists have major "indirect anti-serotonerigc" effects!