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S & R enantiomers of dissociative anaesthetics (NMDA antagonists) & opioids question.

Nagelfar

Nagelfar

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S & R enantiomers of dissociative anaesthetics (NMDA antagonists) & opioids question.

First is first, the point where these questions touch in this topic would be DXM/DXO and the morphinans, but my initial question is about ketamine in-fact.

How is esketamine in comparison to ketamine, and is regular "ketamine" both the R & the S enantiomer with only the S being active? If so does the R enantiomer have any activity whatsoever? (My latter link should be expounded upon at that link to help elaborate the distinction and what is important about it as the latter link is on that difference specifically and "special K" ketamine is a rather widely known substance as a recreational drug) I know one being the active purposed oriented molecule for the effect is the case with SSRI Celexa/Citalopram with Lexapro/Escitalopram being the only one which is in-fact a SSRI.

The second question is I know the other kind of chirality; d- & l-, marks the difference between DXM style NMDA receptor antagonists and opiate style mu receptor agonists (with additional structural differences here or there otherwise but the bulk of the structure changing between those two sets of activity on the dextro- & levo- rotatory isomers of one another....) Well does the chirality of the R & S enantiomers of morphinan opioids change the activity of the morphinan affect on the mu receptors? Is only one active? Does, for example, the morphine molecule proper that grows on the opium poppy crop up both R & S or just one or the other? And if one were isolated would it be more effective or the alternate one made from scratch artificially, if non-extant in nature, have any ulterior effect?
 
(R)-ketamine is active, just has subtly different effects...actually ketamine is one of the rare examples (like MDA) where both isomers are active and have subjectively distinguishable effects, and consequently the pure (R), (S) and racemic mix are all active, and have different effects from each other.

The "unnatural" isomer of morphine is not found in the plant, but has been synthesised and is inactive (as a mu agonist at least). Sinomenine is a natural product which has a morphinan skeleton turned round the "wrong" way but its pharmacology is quite different.
 
well the dextro-rotatory morphinan is close to DXM am I correct? In terms of R & S conformation, which would morphine be? Interesting that R ketamine is active, does anybody have a breakdown about what can be attested to as the differences in effects?
 
R & S mark absolute configurations, and each stereocenter of a molecule can be defined as R/S. Morphine has several stereocenters so it can be assigned multiple R/S codes.

On contrast, Ketamine only has one stereocenter so it can be described simply as R or S.

Dextro/levo are stereoisomers, ie. mirror images of each other - that means that all the stereocenters in dextro/levo pairs are opposite. Morphine is levorotary, as opposed to DXM which is dextrorotary.
 
To make it 'easier', if I'm not mistaken dextro is also sometimes designated (+) and levo (-) as is the case for ketamine. Actually I don't know if it's correct to say S-d-ketamine and R-l-ketamine instead of S-(+)-ketamine and R-(-)-ketamine. I think not, then it would just be d-ketamine and l-ketamine.

If anyone can explain why some compounds are known by their stereoisomeric division like ketamine and others by optical rotation like amphetamine, please do.
 
IIRC, dextro/levo is based on the way a compound rotates polarized light. If it rotates clockwise it's dextro, counterwise = levo.

If a compound is chiral but does not rotate light ie. is not optically active then it has no dextro/levo notation.

To make it even more confusing, there is also the D/L notation which is different than dextro/levo...
 
I still dont really understand.. after having checked this page it doesn't follow when which nomenclature is used as the more important one.

I can only conclude from this that it is just a historic coincedence that with ketamine the name is most often denoted with S/R and sometimes also +/- while amphetamine isomers are denoted with dextro (d) and levo (l).

As far as I can tell it could have just as easily been the other way around but for some practical reason probably the emphasis is put differently, or its just copied by everyone that way.
 
From what dread said above, I just assume ketamine doesn't rotate light, therefore it would be a misnomer to say dextro or levo, and that is why it has the R & S notation.

However could someone explain the D- L- (rather than d- l-) notation?
 
Well, I've seen methamphetamine referred as S/R, +/- and dextro/levo.

So I guess there's really no steady rule for "monostereomeric" compounds (ie. compounds with one stereocenter). With diastereomers, cis/trans is sometimes used in conjunction with dextro/levo, but when the stereocenters go up to 3 then S/R seems to be almost always used.

Oh and to add even more confusion... there's this weird alpha/beta notation for some compounds that have a chiral center as part of a ring system...
 
Ketamine has a chiral centre by virtue of having the =O on the cyclohexyl ring, but funnily enough if you put the =O on the carbon opposite the chlorophenyl and methylamino groups, you're back to a compound with no chiral centres.

Tiletamine retains a chiral centre but PCP, PCE, PCPyr etc all lack one. It's due to the order you'd meet the =O bonded carbon if determining absolute configuration
 
mad_scientist said:
actually ketamine is one of the rare examples (like MDA) where both isomers are active and have subjectively distinguishable effects, and consequently the pure (R), (S) and racemic mix are all active, and have different effects from each other.
Click to expand...
Good point!
Tramadol is another opioid-example, where both isomers produced during the synthesis contribute to the total effect. The one was mainly a µ-agonist, the other a DA-/NE-releaser IIRC. It's also one of the few examples where the racemnic mixture is not just tolerated but indeed desired, due to the synergistic combination of the isomer's effects.


Solipsis said:
Actually I don't know if it's correct to say S-d-ketamine and R-l-ketamine instead of S-(+)-ketamine and R-(-)-ketamine. I think not, then it would just be d-ketamine and l-ketamine.
Click to expand...
Yes, S-d-ketamine = S-(+)-ketamine would be correct, but such way of naming it is really uncommon.


Solipsis said:
If anyone can explain why some compounds are known by their stereoisomeric division like ketamine and others by optical rotation like amphetamine, please do.
Click to expand...
I guess this has mainly historical reasons. The direction of optical rotation can be determined much easier than the absolute configuration; amphetamines are much older than ketamine and origin from an era when optical rotation was the determining property.
Also, it depends on what kind of information you like to provide. Remember that there's no fixed relation between R/S and +/-!


Nagelfar said:
From what dread said above, I just assume ketamine doesn't rotate light, therefore it would be a misnomer to say dextro or levo, and that is why it has the R & S notation.
Click to expand...
Wrong. Ketamine has exactly one stereocenter and therefore is a) chiral and b) does rotate the oscillations plane of polarized light. Not talking about the racemate, of course.


Nagelfar said:
However could someone explain the D- L- (rather than d- l-) notation?
Click to expand...
D/L is Fischer-nomenclature. In contrary to the CIP-system (i.e. R/S; abbreviated from Cahn, Ingold & Prelog, its inventors), which is an absolute way of describing the stereochemistry, Fischer's nomenclature is a relative one; the molecule which was randomly chosen as orientation is glycerinealdehyde. D/L-nomenclature is obsolete and nowadays almost exclusively used for naming sugars and amino acids (this has practical reasons).


dread said:
With diastereomers, cis/trans is sometimes used in conjunction with dextro/levo, but when the stereocenters go up to 3 then S/R seems to be almost always used.
Click to expand...
Again, it depends on what you want to say. The direction of light's rotation results from the combined effects of all 3 stereocenters (to stick a second with your example), whichever these may be. Therefore you can indeed name it d/l resp. +/-. BUT: This doesn't tell a thing about the 3-dimensional configuration. To describe that you'd choose the R/S-system, of course. This must not be confused.


dread said:
Oh and to add even more confusion... there's this weird alpha/beta notation for some compounds that have a chiral center as part of a ring system...
Click to expand...
In this case, the alpha/beta-descriptor is used to name the stereochemical configuration in relation to another stereocenter in the same molecule (not necessarily the only further one). With sugars, where this system is mainly used, the reference atom is usually the last chiral center in the chain, i.e. in glucose and fructose C5, in ribose C4.
NOT to be confused with the way of naming the relative position of a functional group or sidechain in the molecule.

Still question?


Peace! - Murphy
 
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I always remember them by the ephedrines: ephedrine = cis, pseudoephedrine = trans.

Although cis/trans nomenclature is not actually used on them...
 
(must now resist the urge to run through Wikipedia and add to each and every chemical infobox alternate generic names based upon alternative rotatory naming systems) :-P
 
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