The Big & Bangin' Miscellaneous Chemistry/Pharmacology Odds N' Ends Thread: Part 3

[AlphaMethylPhenyl]

So are we pretty clear that oxycodone being synthesized out of thebaine doesn't have to do with it's reported, phenomenally stimulating effects, compared to most other opioids? If so, what might be at play here in this stimulation that many report?

My guess would be higher than usual binding to the delta subtype, as I know it can lower the siezure threshold and thus is likely stimulating.

I know that this is very reductive, though, that psychopharm is terribly incomplete as a science, so am unsure what to think.

 

[ungelesene_bettlek]

May I kindly ask someone (or even more people) to take a short look at this post of mine?

Another question: sometimes I heared either here or at the blacklight forum that the NMDA-antagonism by arylcyclohexylamines is directly intertwined with its dopamine reuptake inhibition. Can someone explain to me in "laymen's terms" what this means? I.e. I do hold a Master's degree in a natural science and almost a PhD, but this field is not directly connected with organic chemistry or psychopharmalogy. Also, I have read here that it also inhibits the reuptake of serotonine and noradrenaline/norephinephrine. Is that true? Also, please explain to me as a laymen what dosage ratios this means.

 

[AlphaMethylPhenyl]

All I can add is that norepinephrine/epinephrine and dopamine are all heavily related, structurally an in terms of metabolism. A significant amount of dopamine is broken down in NE, which is broken down into E. Where one is, the other is, to differing extents. All NRIs at high doses have some DA uptake, as well. So definitely where there's DA reuptake inhibition, there will be NE and E reuptake inhibition.

I haven't read that the DRI capabilities stem directly from NMDA antagonism. Can you list a source? Otherwise, deductively speaking, any recreational drug involves dopamine activity in the limbic region of the brain. As for DRI, I know not. I can definitely say that it's not responsible for the main, extended antidepressant profile of ketamine and other poten NMDA antagonists.

 

[ungelesene_bettlek]

All I can add is that norepinephrine/epinephrine and dopamine are all heavily related, structurally an in terms of metabolism. A significant amount of dopamine is broken down in NE, which is broken down into E. Where one is, the other is, to differing extents. All NRIs at high doses have some DA uptake, as well. So definitely where there's DA reuptake inhibition, there will be NE and E reuptake inhibition.

OK, thank you a lot for that information!

I haven't read that the DRI capabilities stem directly from NMDA antagonism. Can you list a source?

Nope, sorry, I was hoping to find that source when I post that question here.

Otherwise, deductively speaking, any recreational drug involves dopamine activity in the limbic region of the brain. As for DRI, I know not. I can definitely say that it's not responsible for the main, extended antidepressant profile of ketamine and other poten NMDA antagonists.

Really? Also classic psychedelics intervene with dopame as you wrote?

 

[AlphaMethylPhenyl]

Dopamine, or maybe more so, the mu opioid receptor, mediate reward. With psychedelics, you must be on a certain wavelength to "unlock" the pleasure. Similarly, you have to be honest to your therapist to get good advice and heal.

 

[Soulfake]

Does anyone know why certain theoretical possible benzodiazepine-analogues have never been made or generally considered? For example every halogen besides iodine is used, the nitro-unit is always on the phenyl-ring at the diazepine core and not on the other phenyl-unit (e.g. in benzos like flunitrazepam, clonazepam, nitrazepam etc.).

3-methyl benzos don't seem to exist besides meclonazepam (which is very good in my opinion, not as good as etizolam which is my nr.1 but it has similar qualities such as a "bright" effect (in contrast to "dark" ones like nifoxipam, lorazepam, phenazepam or all the RC -zolams with 2 halogens like Flubromazolam, Flualprazolam etc.), a decent half life which lingers minimally into the next day but without the known benzo depressions and it has a broad dosage-spectrum and recreational window as you can feel it from 1mg+ with light anxiolysis/disinhibition and the feeling of being "free" but even 10mg wont make you black out, just very wobbly as the muscle relaxation increases. I loved this effect also from etizolam, you feel heavily relaxed and comfortable but without this drowsy hypnotic sedation of some other benzos)

What about methoxy- or methyl substitutions on one of the phenyl rings? Would they still be active or generally too weak or something else? Could you replace the phenyl completely with something else like norbornane in the image below?
Or for example that cyclohexene-ring that is known from tetrazepam and the pyridine ring of bromazepam are only used in those two benzos except pyrazolam.

Btw., are there any benzos (pharmaceutical or from research papers etc.) that don't have any halogen substitutions at all?

If anyone knows something about this or has links to research papers or something similar I'd be thankful

(The "R" below on the molecules is just a placeholder for whatever substitution one could (also) make there)

edit: I have another question; there are new cannabinoids on the market which have instead of the usual pentyl-side chain a "pentenyl"-chain. Can anyone guess what difference this creates? It looks like a too simple modification to be also safe as it hasn't been used until now, if it would be that easy than you could have just replaced the pentyl chains of the old cannabinoids with pentenyl's so I have the feeling that there must be a hitch to this kind of analogue, although it seems there are cannabinoids in the JWH-series that also have this kind of side chain but why is it only used now? Does it impact the molecule in a unforseeable way or make it more/less active?

 

[polymath]

Anyone heard about this kind of alkaloids before?

Akuammicine - Wikipedia

en.wikipedia.org

Opioid activity of alkaloids extracted from Picralima nitida (fam. Apocynaceae) - PubMed

Extracts of the seeds of Picralima nitida (fam. Apocynaceae) have been reported to have opioid analgesic activity. In this investigation, isolated tissue bioassays and radioligand binding assays have been used to determine the opioid activity of five alkaloids--akuammidine, akuammine...

www.ncbi.nlm.nih.gov

Abstract
Extracts of the seeds of Picralima nitida (fam. Apocynaceae) have been reported to have opioid analgesic activity. In this investigation, isolated tissue bioassays and radioligand binding assays have been used to determine the opioid activity of five alkaloids--akuammidine, akuammine, akuammicine, akuammigine and pseudoakuammigine--extracted from the seeds of P. nitida. Akuammidine showed a preference for mu-opioid binding sites with Ki values of 0.6, 2.4 and 8.6 microM at mu-, delta- and kappa-opioid binding sites, respectively. The agonist actions of akuammidine in the mouse-isolated vas deferens were antagonised by naloxone and the mu-opioid receptor selective antagonist D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP) confirming an action at mu-opioid receptors. In contrast, akuammine also showed highest affinity for mu-opioid binding sites (Ki 0.5 microM) but was an antagonist at mu-opioid receptors with a pK(B) of 5.7 against the selective mu-opioid receptor agonist [D-Ala2,MePhe4,Gly-ol5]enkephalin (DAMGO). Akuammicine has the highest affinity for kappa-opioid binding sites (Ki 0.2 microM) and was a full agonist at kappa-opioid receptors in the guinea pig ileum preparation but a partial kappa-opioid receptor agonist in the vasa deferentia of the mouse and the rabbit. Akuammigine and pseudoakuammigine showed little or no efficacy in the opioid bioassays. None of the alkaloids had significant activity for opioid receptor-like binding sites (ORL1-binding sites) with Ki values >> 10 microM. These data show that some alkaloids extracted from the medicinal plant P. nitida possess varying degrees of agonist and antagonist activity at opioid receptors but possess neither high affinity nor selectivity for mu-, delta- or kappa-opioid receptors or the ORL1-receptor.

I wouldn't extract this stuff from the Vinca plants, though, as some of the vinca alkaloids are quite toxic cytostats used in cancer treatment.

 

[FormerBeagle]

If anyone knows something about this or has links to research papers or something similar I'd be thankful

Electronegative substituents are needed at the 7th position (R in your figure). Given the number of these that have appeared on the market and the many billions of dollars that market has generated over the last 60 years or so, ring substitutions other than phenyl have undoubtably been looked at. Foye’s Medicinal Chemistry has a chapter with a nice overview of benzo SAR.

I have another question; there are new cannabinoids on the market which have instead of the usual pentyl-side chain a "pentenyl"-chain. Can anyone guess what difference this creates?

If the pentenyl substituent serves the same function in this series as in the traditional cannabinoids, increases in lipophilic character here increase activity. For instance the dimethyl-heptyl analog of THC. The double bond would serve that function. It also would presumably serve to protect it from omega and omega-1 metabolic hydoxylation. I doubt that was the rationale though.