Dextro-Methadone

[Gaz_hmmmm]

Why is it not used as an anesthetic? For those that don't know Dextro-Methadone is an NMDA antagonist, whilst Levo-Methadone is a Mu-Opioid receptor agonist.

Methadone is really cheap to make, about £2 (Less then $5) for a gallon of 1mg/1ml and I can't imagine seperating the levo from the dextro to cost that much and the company would be easily able to sell the 'excess/unwanted' levo-methadone.

I've tried looking for info' on it and can't find much really.

 

[sekio]

Seperating the enantiomers of a molecule is not as trivial as you make it seem. At the very least you have to pay chemists to hang around and do more work, and quite often it is not worth your time and money to sell the inactive isomer.

In addition, dextro-(S)-methadone has a much higher affinity for the hERG potassium channel, an antitarget of most drugs and known to cause long QT syndrome. It's responsible for mathadone's enhanced cardiotoxicity and for this same reason levo-acetyl-methadol was shot down as well.

So in short the reason it's not seen is because it's more toxic than the racemate and it takes too much effort to seperate it.

 

[ebola?]

Also, I doubt that an NMDA antagonist with a duration like l-methadone's would be particularly medically useful. Drug naive patients don't want to feel fucked up for a day or more after coming out of anaesthetic.

Also, 2d diagrams of methadone look like bicycles!

ebola

 

[dopamimetic]

What I have wondered repeatedly is, why does d-Methadone not only not help with tolerance like other NMDA antagonists, but is rather said to cause withdrawal-like symptoms which cease when people switch to pure l-Methadon ...? So it just being too weak at antagonizing NMDA is not enough to explain, does it have strong activity at other (lesser known) sites?

Or does this differ between individuals (genetically) and NMDA antagonism only helps some while causing problems for others?

 

[endotropic]

NMDA antagonists are only used as anesthetics when inhalation anesthetics aren't appropriate, like in third world countries where you don't have all the equipment to closely monitor vital signs and the money to pay a dedicated anesthesiologist. The NMDA antagonists cause a much more distressing patient experience (think coming out of a K-hole + medical environment + surgical pain + all the fear that goes along with that), so despite the fact they're safer than inhalation anesthetics in general, they're really not used that often.

Ketamine is also very cheap to make, has a long proven track record of safety, few drug interactions (and we know the ones that do occur), manageable duration of action, and causes a flaccid paralysis unlike older NMDA antagonists like PCP that cause muscle rigidity. It's basically the perfect anesthetic already, nightmares aside.

 

[serotonin2A]

There is evidence that the anesthetic effects of ketamine are due to effects on Ih (HCN) channels and this effect may be independent of NMDA blockade. So NMDA blockade may not be sufficient to produce surgical anesthesia that is tolerated by patients.

 

[endotropic]

There is evidence that the anesthetic effects of ketamine are due to effects on Ih (HCN) channels and this effect may be independent of NMDA blockade. So NMDA blockade may not be sufficient to produce surgical anesthesia that is tolerated by patients.

PCP was also used as an anesthetic in the 50's. I don't think PCP has the same effect on HCN channels but I could be wrong. I would guess all NMDA antagonists could work as anesthetics at the right doses, with some working better or worse due to off target effects.

 

[serotonin2A]

PCP was also used as an anesthetic in the 50's. I don't think PCP has the same effect on HCN channels but I could be wrong. I would guess all NMDA antagonists could work as anesthetics at the right doses, with some working better or worse due to off target effects.

You are certainly correct. PCP and a few other NMDA antagonists (etoxadrol, dexoxadrol) act as anesthetics. But most patients couldn't tolerate their effects. By contrast, that isn't the case with ketamine. The fact that ketamine can induce sedation through both NMDA and non-NMDA mechanisms may be one reason why it is better tolerated than PCP or MK-801 (ie, you don't need as high a level of NMDA blockade to induce anesthesia, so emergence reactions are less severe).

 

[dopamimetic]

Okay, but what I meant is not the general use as an anaesthetic but the point that NMDA antagonists do help many people with keeping tolerance down or lowering withdrawal symptoms ... I am on memantine 40mg/d and while I know it's playing with fire (and so I'm limiting it strongly), I seem to be able to use opioids daily with barely any tolerance development and no w/d when ceasing.. I don't dose too high, as I don't use them for euphoria but more as a mental pain killer, but still.. There are threads here on bluelight about this topic with many postings.. seems not to work for everybody, but for these who it's working, it's amazing..

 

[serotonin2A]

I guess I'm not really sure why you would assume that a drug company would want to develop d-methadone for this purpose. Think of the following points:
(1) Is there any reason to think d-methadone is actually a very effective NMDA antagonist in people? When people take methadone, they don't seem to display signs of NMDA blockade. Some blockade may be occuring, but is it really a substantial effect?
(2) Are there off-target effects of d-methadone that make it a poor choice for development? If d-methadone has cardiac effects then it would not be a very good drug candidate.
(3) To make d-methadone, you have to seperate it from dl-methadone, which is a controlled substance. That's never a helpful thing in terms of drug development. And it's probably not a simple process to seperate the isomers on a large scale.
(4) Drug development seldom moves forward if there is no patent protection.
(5) Why develop d-methadone and not another NMDA antagonist with none of the drawbacks listed above?
(6) Is there enough of a clinical need to develop new drugs for this indication? Can d-methadone be sold for enough money and to enough patients to recoup development costs?

 

[Limpet_Chicken]

What are HCN channels?

 

[serotonin2A]

HCN channels are "hyperpolarization-activated cyclic nucleotide-gated" channels. They are excitatory channels that are activated when the cell membrane is hyperpolarized and inactivated by depolarization. They tend to be involved in generating pacemake activity--basically repetitive neuronal firing. However, HCN channels can also inhibit neuronal excitation under certain conditions by interacting with other channels.

HCN channels mediate a current known as Ih (physiologists used to name channels based on the characteristics of the effects they produce, because until recently little was known about the structure of the channels).