Emerging data on properties and pharmacophore of DRIs

[aced126]

Based on these few compounds, there seems to be evidence that neither an aliphatic nitrogen 3-4 angstroms away from the aromatic nor a beta ester is crucial for (S)NDRI activity, but rather shape of the molecule itself plays a much bigger role than originally thought.
https://en.wikipedia.org/wiki/Desoxypipradrol
https://en.wikipedia.org/wiki/O-2172
http://pubs.acs.org/doi/abs/10.1021/jm0205292
In the above study it also shows how a nitrile group is bioisosteric for a methyl ester, suggesting the nitrile group (even though the lone pair is of much lower basicity) could be acting in place of the aliphatic nitrogen itself.
This is the compound I am talking about:

Inhibition of B-CFT binding to DAT ic50 is 127 nanomolar. Methylphenidate is 17 nanomolar, for comparison.
This begs the question, what would the ic50 value of this compound be?

What about just this simple compound? I suspect it could also have MAO inhibitory activity:

Moving on from that and addressing the original topic, could it be possible for a potent DRI to exist which just has a carbon skeleton?

If they are found to be efficacious at blocking DAT, then they would probably have some serious pharmacokinetic problems like maybe being excessively deposited into fat tissue (and it seems a bit weird taking hydrocarbons as a medicine) but that nevertheless is still rather absurd to me of this possibility of a simple hydrocarbon skeleton. Does anyone know of any drugs on the market at the moment which consist of just carbon? I don’t know of a single one.

 

[serotonin2A]

It has been known for some time that a basic nitrogen is not required for binding to DAT: http://www.ncbi.nlm.nih.gov/pubmed/10638825 This reinforces the viewpoint that there are almost always multiple ways for ligands to engage with the residues that make up a binding site.

 

[dopamimetic]

Moving on from that and addressing the original topic, could it be possible for a potent DRI to exist which just has a carbon skeleton?

This is desoxypipradrol without the nitrogen, and according to serotonin2A it should work too then- but would it enter the brain?

 

[aced126]

Normally as you increase lipophilicity of a drug it crosses into the BBB more and more, but it gets to a point (which I think might be the case here) where it is too lipophilic that it gets excessively deposited in certain tissues because it crosses across lipid membranes with great ease.

Another thing is that, although a nitrogen is not necessary for activity, and neither is a carbomethoxy group, it certainly does help. As you can see ring substituents contribute greatly to activity as well (threo-3,4-dichloromph has an ic50 of 5nM). So my fear is that when all of these are removed, the compound will lose great efficacy, and at dosages required to gain a response it's going to start acting on other targets.

 

[serotonin2A]

This is desoxypipradrol without the nitrogen, and according to serotonin2A it should work too then- but would it enter the brain?

I'm not sure if it would work -- in the absence of a basic nitrogen, there would have to be some other interactions that could substitute for the loss of binding energy. For example, in the cocaine analogs where the amine was replaced with oxygen, the oxygen could potentially act as a H-bond acceptor. It's not clear if this desoxypipradol analog without the nitrogen would have substantial affinity. The only way to know is make it and run a binding assay, or potentially you could dock it in a transporter model.

 

[aced126]

Does anyone know of any drugs currently being prescribed which consists of just a carbon skeleton?

 

[Nagelfar]

My question is: how would a DRI ligand lacking the nitrogen be protonated? Cocaine is insoluble unless it's the salt form, for example; usually hydrochloride, it's the nitrogen that gets protonated which turns it from being insoluble to being highly soluble; I've wondered this about the 8-oxa substituent analogs of cocaine that still show some efficacy in vitro; how'd that bode in-vivo / &/or be protonated exactly?

 

[serotonin2A]

My question is: how would a DRI ligand lacking the nitrogen be protonated? Cocaine is insoluble unless it's the salt form, for example; usually hydrochloride, it's the nitrogen that gets protonated which turns it from being insoluble to being highly soluble; I've wondered this about the 8-oxa substituent analogs of cocaine that still show some efficacy in vitro; how'd that bode in-vivo / &/or be protonated exactly?

It wouldn't be protonated. Protonation isn't always a requirement for drug activity. Freebase cocaine is a very active drug unless you administer it through a route that requires it to dissolve in an aqueous solution.

 

[Nagelfar]

It wouldn't be protonated. Protonation isn't always a requirement for drug activity. Freebase cocaine is a very active drug unless you administer it through a route that requires it to dissolve in an aqueous solution.

So 8-oxa derivatives in this case cannot be the salt form through whatever means, in short?

 

[serotonin2A]

So 8-oxa derivatives in this case cannot be the salt form through whatever means, in short?

Not unless there was a basic nitrogen added somewhere else in the molecule.

 

[farmacista]

Does anyone know of any drugs currently being prescribed which consists of just a carbon skeleton?

cyclopropane has been used as an anaesthetic but i don't think there are any drugs currently prescribed

 

[Friman1987]

I think such structures that lacking amino/hydroxyl groups can induce cancer. Benzene can cause cancer. The same applies for many other kinds of aromatic structures. These kind of structures are very lipophilic, and as steroids should easily get into the cell membrane and nucleus, and this is not something you want.

They cannot be metabolized so easily. The metabolites also tends to be dangerous.

 

[serotonin2A]

I think such structures that lacking amino/hydroxyl groups can induce cancer. Benzene can cause cancer. The same applies for many other kinds of aromatic structures. These kind of structures are very lipophilic, and as steroids should easily get into the cell membrane and nucleus, and this is not something you want.

They cannot be metabolized so easily. The metabolites also tends to be dangerous.

Actually, the metabolites are what tend to be carcinogenic, not the parent aromatic molecules. Benzene is carcinogenic due to epoxide metabolites, which can interact with DNA. But you can't generalize to all aromatic hydrocarbons -- toluene and xylene are closely related molecules that are non-carcinogenic.

But you are correct that it is generally a good thing for dugs to have hydrophobic groups as a metabolic handle. The last two structures the OP gave are poor candidates for human use. I think it is a bad idea to develop stimulants that would linger in the body due to slow metabolism and excretion-- there might be residual stimulation that lasts for days.

 

[aced126]

But you are correct that it is generally a good thing for dugs to have hydrophobic groups as a metabolic handle. The last two structures the OP gave are poor candidates for human use. I think it is a bad idea to develop stimulants that would linger in the body due to slow metabolism and excretion-- there might be residual stimulation that lasts for days.

Did you mean hydrophilic?Having considered these points, I'd have to agree with them. Yes, the long half live would cause considerable residual stimulation. Furthermore the only metabolic labilities on the aromatic hydrocarbons I posted are of course epoxidation and subsequent ring opening, as well as hydroxylation on the benzylic carbon. With that said, if we could somehow promote the latter metabolic modification, the drug molecule is less likely to form reactive epoxide species which could lead to DNA intercalation. Furthermore it will have a shorter half life.

To illustrate:

The aromatic halogen substituents should reduce reactivity of the aromatic rings such that epoxidation should not occur to a great extent, but rather hydroxylation at the benzylic carbon. The only disadvantage is that the resulting alcohol in this case is tertiary; it should be primary preferentially so that in can be further oxidised fully to the carboxylic acid derivative for easy excretion (this is why toluene is less carcinogenic than benzene - it is oxidised to benzoic acid which is easily excreted). Furthermore, the fluorines are placed meta to the benzylic carbon such that they do not destabilise the resulting intermediate.
So, using this principle, the following metabolic handles can be incorporated to reduce the molecule's potential carcinogenicity as well as reduce half life.

All 3 benzylic carbocations (especially the tertiary one) are stabilised by the para electron donating groups each of them have (ortho EDGs can do this as well), thus making reaction at the benzylic carbocation more likely to happen. Obviously one could argue that the ring itself is activated and is more likely to form reactive epoxides, but from the observation of toluene being less carcinogenic than benzene, we know that benzylic carbocation stabilisation is more important than having an activated ring.

 

[Friman1987]

Cocaine blocks the DAT outside the cell, on the cell membrane. These molecules will pass the cell membrane (tPSA = 0, logP = 6,93) and should not produce the same effect. The effect is not so predictable.


I Am not sure how safe toluene and xylene is if you consume them as a drug. There are different opinions about this.

Metabolism:

https://en.wikipedia.org/wiki/Toluene_toxicity
There is a risk for cancer, maybe 1% lol. Enzyme polymorphism should make the % higher/lower.

Cancer is not the only problem.

Effects of long-term exposure of toluen:
Psychoorganic syndrome; visual evoked potential (VEP) abnormality; toxic polyneuropathy, cerebellar, cognitive, and pyramidal dysfunctions, optic atrophy; and brain lesions.
There is some evidence that low-level toluene exposure may cause disruption in the differentiation of astrocyte precursor cells.[24] This does not appear to be a major hazard to adults; however, exposure of pregnant women to toluene during critical stages of fetal development could cause serious disruption to neuronal development.[24]
The neurotoxic effects of long-term use (in particular repeated withdrawals) of toluene may cause postural tremors by upregulating GABA receptors within the cerebellar cortex.[22] Treatment with GABA agonists such as benzodiazepines provide some relief from toluene-induced tremor and ataxia.[22] An alternative to drug treatment is vim thalamotomy.[22] The tremors associated with toluene misuse do not seem to be a transient symptom, but an irreversible and progressive symptom which continues after solvent abuse has been discontinued.[22]

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

 

[aced126]

BTW, meta-cresol would not be produced in any significant amounts (the methyl group stabilises ortho and para hydroxylation). Yes, of course these molecules have a high logP; they'll be able to cross cell membranes easily. Having said this, the logP scale is of course a logarithmic scale. There are many molecules designed to interact with receptors on a synapse with very high logPs yet they don't enter cells in significant amounts. The rate at which amphetamine enters cells via DAT uptake is much higher than the rate of diffusion across the plasma membrane. If the molecule can form good interactions with the receptor, it will bind to it.

 

[serotonin2A]

There is a risk for cancer, maybe 1% lol. Enzyme polymorphism should make the % higher/lower.

Cancer is not the only problem.

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

Citation? I haven't seen any data supporting this view. The current EPA conclusion is pasted below.

"Available studies in workers have reported limited or no evidence of the carcinogenic potential of toluene. Similarly, the few available epidemiological studies have failed to demonstrate increased risk of cancer due to inhalation exposure to toluene. However, these studies were limited due to the size of the study population and lack of historical monitoring data. Chronic inhalation exposure of rats did not produce an increased incidence of treatment-related neoplastic lesions. Uder the Guidelines for Carcinogen Risk Assessments (US. EPA, 2005), the EPA considers that there is inadequate information to assess the carcinogenic potential of toluene"

 

[Friman1987]

I saw That 1% of the toluene is metabolized to p-cresol. Therefore, there is a chance that You will get the formation of an epoxide. Which can cause cancer if you have benzene. 1% maybe not makes any difference. This is just a speculation. Otherwise I can not find any articles about this.

 

[aced126]

Of course you are right in saying this; there is a very small proportion of epoxide intermediates when the body metabolises toluene. Compare this to benzene, however, where pretty 100% of it would need to be metabolised via an epoxide intermediate, which is probably why toluene is significantly less carcinogenic than benzene. I wonder if tert-butylbenzene would present a significant carcinogenic risk similar to (or even greater than) benzene itself.

 

[Friman1987]

Yes, there is a chance that it does.

Maybe something like that happens?

Otherwise T-butyl should metabolize in the same way as toluene.

Something like this: http://patentimages.storage.googleapis.com/WO2003064391A1/imgf000043_0001.png