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D-morphinans-any reports?

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Limpet_Chicken

Bluelighter
Joined
Oct 13, 2005
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Now, an off the cuff remark in my recent thread about halomorphides, concerning the stereochemistry of them and derivatives, got me thinking. The dextro-isomers are often NMDA antagonists, whilst the laevo- are the opioids. I could easily get hold of PCl5, PCl3 or sulfuryl chloride to attempt stereochemical inversion.

Also, does potency as NMDA antagonist of the D-isomer of the phenanthrene opioids correlate at all with potency as a MOR agonist of the corresponding L-isomer? that is to say, do the more potent opioids in the family result in more potent NMDA antagonists? just curious really. But it would be interesting enough to sample the D-isomers of any of the common, or less common ones anyway regardless.
 
Limpet_Chicken said:
Now, an off the cuff remark in my recent thread about halomorphides, concerning the stereochemistry of them and derivatives, got me thinking. The dextro-isomers are often NMDA antagonists, whilst the laevo- are the opioids. I could easily get hold of PCl5, PCl3 or sulfuryl chloride to attempt stereochemical inversion.

Also, does potency as NMDA antagonist of the D-isomer of the phenanthrene opioids correlate at all with potency as a MOR agonist of the corresponding L-isomer? that is to say, do the more potent opioids in the family result in more potent NMDA antagonists? just curious really. But it would be interesting enough to sample the D-isomers of any of the common, or less common ones anyway regardless.
Click to expand...
One of bluelights rules is supposed to be no synthesis discussion. I think this would extend to all of your recent posts that I have seen, where you are discussing synthetic work that you can perform. It is one thing to discuss theoretical aspects of synthesis, but you are discussing this personally--including what reagents you can obtain--and I think it is completely off-topic. I also have to question the motivations of someone who would unecessarily but repeatedly incriminate themselves.

Regarding your second question, for the potency to correlate, there would have to be parallel structure-activity relationships. Opioids and NMDA-R antagonists obviously have different SAR, including the fact here that the stereochemistry of binding is inverted. The structural changes that make a potent MOR agonist are detrimental for NMDA-R blockade.
 
Inverting one stereogenic centre is not going to invert the other 4.
 
Yes thats what I was wondering, if there was any positive or negative correlation between potency at MOR and the potency at NMDARs for the corresponding D-isomers.
If as you say, the changes that make for more potent opioids do the opposite for NMDA antagonists, does the inverse of this also follow-that generally speaking changes made to the morphinan skeleton that decrement opioidergic potency of the L-isomer, conversely make, potentially for better NMDA antagonists (such as for example, dihydrocodeine)

Which particular stereocenter is that which determines MOR vs NMDAR binding?
and yes I am aware of that.
 
All 5 of them it seems. Of course the 6-OH and ether bridge can be entirely removed, leaving only 3 stereogenic centres left. Nevertheless, all 3 of the remaining need to be inverted. You need the enantiomers of normal morphinans for NMDA antagonism.
 
Limpet_Chicken said:
Yes thats what I was wondering, if there was any positive or negative correlation between potency at MOR and the potency at NMDARs for the corresponding D-isomers.
If as you say, the changes that make for more potent opioids do the opposite for NMDA antagonists, does the inverse of this also follow-that generally speaking changes made to the morphinan skeleton that decrement opioidergic potency of the L-isomer, conversely make, potentially for better NMDA antagonists (such as for example, dihydrocodeine)
Click to expand...

There isn't really any set relationship between affinity for the PCP site and MOR -- it just so happens that there is some SAR overlap, meaning that some compounds (or their stereoisomers) happen to have high affinity for both sites.
 
Hey Limpet sorry if you're already aware of Levorphanol but I just thought I would point out it's existence if you're wondering about morphinan MOR agonists/NMDA antagonists. I don't recall how much NMDA affinity it has though.
 
Ahh indeed I was aware of it. Just been boning up on derivatives, after wondering if the morphinan backbone would take severe de-aromatization. That came as the result of an ADD-tendencies-laden psychic hop from reading up on calcium and strontium in birch reduction systems. A dual MOR1 agonist/NMDA antagonist would doubtless push all the right buttons so to speak. Actually, aside from certain efforts aimed towards acylating opium isolates, and dipropionylmorphine, methadone is my other favourite opioid. That I've tried of course.

Can the ring that normally in morphine's case bears the 6-position OH, be dearomatized and retain activity?

Also, how does changing the halide affect potency, if at all? unless there is compelling reason to fluorinate, lets just not and say we did.
 
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