Tesofensine

[djsim]

Tesofensine: (2R,3S)-3-(3,4-dichlorophenyl)-2-ethoxymethyl- 8-methyl-8-azabicyclo[3.2.1]octane

There's been alot of news coverage lately regarding this drug. Going thru phase III trials right now.
It resembles cocaine, except the ester isn't there (so much longer half life I assume), there is Dicholoro at 3,4 positions on phenyl, and cocaine's methyl ester is replaced with methyl ethoxy moeity.

I am a bit hazy on SARs for tropanes, so can anyone tell me what these changes would make? The dicholoro for instance... does this increase or decrease potency (relative to tropane stims such as cocaine)

BTW- semi-recent study in the Lancet says that test subjects lost almost 13kg in 6 months using this drug. Media is having a field day calling it "the possible cure for obesity" 8) (according to Herald Sun, Australia). It's a NA/5HT/DA reuptake inhibitor.

PS, just out of interest... the [3.2.1]octane part of the chemical name... what does that mean again? And where do they start counting the octane from?

 

[Pomzazed]

the [3.2.1]octane part is bicyclic numbering system which writes
[x.y.z].....ane, where when you dont count the bridgehead carbon, the x indicates number of carbon in "larger" side, y on "smaller" size and z for the bridge.

in this case it indicates the tropane ring! (8-aza = nitrogen at #8 position)

 

[mad_scientist]

3,4-dichloro substituent on the phenyl ring is one of the most potent substitutions in this class, and intrinsic toxicity shouldn't be too much of a concern (bromo or iodo are more potent than chloro but come off too easily which can produce toxic metabolites)

Ethoxymethyl is not a 2-position substituent I've seen used much in phenyltropanes but has the right characteristics to give decent binding affinity (i.e. flexible so can easily adopt good binding conformation, oxygen lone pair in right position, good lipophilicity characteristics).

Usually the 2β enantiomer is more potent than 2α, but in this case I'd say the 2α has been selected to give the "triple reuptake inhibitor" profile they were after, most likely the 2β,3β would be much more DAT selective rather than binding to all three monoamine transporters.

You can see the high potency of the drug from the dose range they were using in the clinical trial, 0.25mg, 0.5mg and 1mg...the 0.5mg dose produced almost as much weight loss as 1mg but without producing the same amount of high blood pressure (which is obviously a concern with obese patients)

I'm betting insomnia will be a problem at high doses, and I'd say the abuse potential should be reasonable as well, this will be an interesting one to watch.

 

[djsim]

the [3.2.1]octane part is bicyclic numbering system which writes
[x.y.z].....ane, where when you dont count the bridgehead carbon, the x indicates number of carbon in "larger" side, y on "smaller" size and z for the bridge.

in this case it indicates the tropane ring! (8-aza = nitrogen at #8 position)

sorry it's been awhile since I did organic chemistry. Which one would the bridgehead atom be?
It's octane because (like other IUPAC names) we found the longest chain and it is 8 carbons, correct? Because it says 3-(3,4-dichlorophenyl)-2-ethoxymethyl-, am I right in saying the counting starts at the carbon next to the N but at the back of the bridge, then the counting ends at the N?
And could you clarify what the larger side etc means?
Sorry guys I know this aint really typical ADD material but I'd like to read this tropane nomenclature as I have been looking into these tropane compounds as of late and would like to be able to picture em without a chemdraw batch file

 

[djsim]

Also, another SNDRI is Brasofensine ((E)-1-[(1R,2R,3S,5S)-3-(3,4-dichlorophenyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-yl]-N-methoxymethanimine)

Quite similar to tesofensine. But Phase II trials were apparently undertaken 12 years ago and never made it to phase III so I cant see how tesofensine could be as good as the media is making it out to be. It's funny because CB1 antagonist rimonabant was just taken off the market in the UK this week too. I cant see how meds like this will kill off the obesity crisis. I think its pathetic how much we (the western world) consumes, then we wonder why we're fat. Dont get me started on this though 8)

 

[djsim]

the [3.2.1]octane part is bicyclic numbering system which writes
[x.y.z].....ane, where when you dont count the bridgehead carbon, the x indicates number of carbon in "larger" side, y on "smaller" size and z for the bridge.

in this case it indicates the tropane ring! (8-aza = nitrogen at #8 position)

OK I think I figured it out (see attachment for numbering... btw it's the top left part, ignore bottom left). Just one Q that has me confused. The ring has 7 carbons. why is it then octane? and the number 8 atom in the pic? that points to the N bridge yes?
Anyway, so the [3.2.1] applies because there is 3 atoms on the left hand-side of the bridge point, 2 atoms on right hand side, and 1 atom (nitrogen) as bridge, right?

Thanks again

 

[fastandbulbous]

bromo or iodo are more potent than chloro but come off too easily which can produce toxic metabolites

Aromatic bromo & iodo groups don't come off at all, metabolically. It requires a round bottomed flask and things like lithium or magnesium (formation of organolithium/Grignard reagents respectively) to remove halogens unless additional ring substituents are present (like 2,4-dinitro)

 

[Pomzazed]

#djsim
Yes, counting the number on the larger side, then smaller, then the bridge and you get the position number.

it's called an octane because this is based on bicyclo[3.2.1]octane, molecule of the same shape but on the bridge is a carbon atom also. -aza- is IUPAC way for calling hydrocarbon with N replaced at C counting the same main chain; thus here you can see -8-aza prefix, making : 8-azabicyclo[3.2.1]octane.

The same also applies to oxygen, with prefix -oxa-; like the one you see in dioxane

 

[Riemann Zeta]

This one might be a good antidepressant, as it seems to retain a little stimulant action (being a 3beta-phenyl-tropane a la b-CFT/RTI-55/b-CIT). The half-life must be amazing, however--maybe not as long as something like desoxypipradrol, but still, without an ester and with the lipophilicity of the 3,4-dichloro moiety.

 

[nuke]

Not sure it's the solution to obesity though... amphetamines can cause similar weight reductions. I think they should be studying oxidative phosphorylation inhibitors and insulinic antagonists more seriously. Obese people need profound weight loss, if you weigh 175 kilos and lose 10 in a month because of a drug you'll probably eventually stop taking, what's the point?

 

[Riemann Zeta]

^True. Any stimulant or monoaminergic agent is only going to be a temporary weight loss solution. The body tends to readily adapt to the peripheral stimulant effects (what I call side effects) but not the central stimulant/cognitive effects of a chronic low-dose amphetaminergic agent.

Right now, exercise is really the only viable solution and it is a solution that takes an incredibly long time to manifest profound effects. Amphetaminergic agents, other psychostimulants and antidepressants aren't magical--their anorectic and thermogenic effects are ephemeral and insignificant in the long run. I think their real benefit is that they can help provide motivation, but it is solely the responsibility of the individual to use that motivation to exercise. And for a lot of people, that just doesn't happen.

 

[dread]

two words.. stomach staple

 

[mad_scientist]

Aromatic bromo & iodo groups don't come off at all, metabolically. It requires a round bottomed flask and things like lithium or magnesium (formation of organolithium/Grignard reagents respectively) to remove halogens unless additional ring substituents are present (like 2,4-dinitro)

I thought they could be detached by CYP enzymes in the liver and react with free SH groups on proteins to form potentially allergenic metabolites...but you may be right and it requires other groups to be attached to the ring as well, been too long since I did toxicology...

The duration of this stuff will be extreme if people try taking big doses to get a recreational effect...the half-life is well over 200 hours, and then it forms an O-dealkylated active metabolite with a half life over 300 hours, so it would probably keep you up for days and days like desoxypipradrol.

 

[djsim]

Another SNDRI I found in the literature is Ro 8-4650 (Diclofensine).

Wikipedia says it may have been discontinued due to abuse potential... I know, I know, never trust Wikipedia, but they provide references for this statement which check out:

• Lamb RJ, Griffiths RR. Self-administration in baboons and the discriminative stimulus effects in rats of bupropion, nomifensine, diclofensine and imipramine. Psychopharmacology (Berlin). 1990;102(2):183-90
• Nakachi N, Kiuchi Y, Inagaki M, Inazu M, Yamazaki Y, Oguchi K. Effects of various dopamine uptake inhibitors on striatal extracellular dopamine levels and behaviours in rats. European Journal of Pharmacology. 1995 Aug 4;281(2):195-203

So as you can see from the structure the it has the methamphetamine skeleton, though this would be very rigid since the skeleton is part of a dihydroisoquinoline skelton.
My question is what determines if something has abuse potential? I mean, why is bupropion not abusable, even though it is inhibits DA reuptake?

 

[LuxEtVeritas]

one reason Bupe has no abuse potential is negative sides manifest at doses approaching any chance for abuse
as well it has properties of inhibition of α3β4 receptors which decrease abuse potential

 

[Hammilton]

It's not a great DARI, either. n-tert-butyl-amps and cathinones are pretty weak (if active at all, no?). The bulk gets in the way of good binding.

 

[Tchort]

It sounds like the risk/reward factor is out of balance. Had any pharmaceutical company hyped up and re-released a slightly tweaked ATS (Amphetamine Type Stimulant) I'm sure the reports of wonderful weight-loss results and quotes like "new cure for obesity" would be floating around it too. Aside from not resembling current ATS diet drugs in structure, I don't see the benefit in studying it.

If the capacity for abuse is anywhere near what it looks like it will be, it would be a CII right out of the gate. I can't see any powerful stimulant with abuse potential gaining much ground in the treatment of obesity. We already have CII drugs for obesity like Desoxyn, CIII drugs like Benzphetamine and Phendimetrazine and CIV drugs like Diethylpropion, all of which are basically in the junk pile; they are very rarely prescribed. Phentermine is probably the only common scheduled weight loss pill, my guess is mainly due to its long status as a non-scheduled drug (now CIV). Discontinued drugs like Pemoline and completely unused obesity drugs like Pipradol, Pyrovalerone and Propylhexedrine litter that same junk pile. Theres no shortage of controlled stimulant diet pills. One more, especially if it is CII or even CIII, isn't going to bring in high enough profit to warrant a decade of research, trials and marketing (heaven forbid if it does catch on in the stimulant abuse community, it could be made CI or just discontinued).

 

[LuxEtVeritas]

On grounds simply that it has CII level abusability if that is found to be so in testing it will be denied as they do not want more/new agents of abusability unless really truly some valid reason which here there is none

 

[vecktor]

the related substance brasofensine has already been scheduled in the UK, with next to no consultation it is not possible to find the correponding statutory instrument SI schedluling these things.

controlled drug list for UK
http://www.homeoffice.gov.uk/documents/cdlist.pdf?view=Binary

so I expect to see tesofensine scheduled, again without proper consultation.


this BTW is the worst list of scheduled drugs I have ever seen, clearly written by an imbecile of a bureaucrat without the faintest chemistry or pharmacological knowledge,

what the fuck is methylene dioxythyl amphetamine, its highly illegal, this whole document is riddled with errors.

sad

 

[Tchort]

this BTW is the worst list of scheduled drugs I have ever seen, clearly written by an imbecile of a bureaucrat without the faintest chemistry or pharmacological knowledge,

what the fuck is methylene dioxythyl amphetamine, its highly illegal, this whole document is riddled with errors.

sad

Hmm...

USA, Pholcodine is Schedule I.

I think we yanks had a bigger idiot write our drug statute :/