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I Like to Draw Pictures of Random Molecules

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PZM21 is a novel opioid that is structurally quite different from the previous examples. But the indicated receptor binding correlations show that it binds to opioid receptors & has an activity level similar to morphine.

Note that the structure in red on the left end of PZM21 is structurally close to that of tyrosine.
PZM21.jpg
 
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Anyone have experience with L-theanine? Available in health food stores & online. One reviewer on Amazon said it made her hypomanic (bipolar). Affects glutamate. I'm leery of trying things like this unless I absolutely have to because sometimes the results can be unpleasant for a long time after.

L-theanine.jpg
 
It relieves caffeine body load, I haven't really noticed any other effects beyond that. I only bought it once, but I've seen other anecdotal reports of anti-anxiety relief.
 
Thanks. It might help with melatonin for sleep if I have to go in that direction. But I have some type of bipolar & that negative report from a former user on Amazon concerns me. A supplement like this that can screw with an NT like glutamate could have nasty effects long after you stop taking it.

On the topic of sleep, I've used Dramamine with varying results. The first time I tried it was just before a night flight on a commuter airplane in bad weather, to prevent motion sickness. Damned if I didn't wake up until the plane had landed on its destination! Things like that catch my attention.

It is closely related to diphenhydramine HCl, or Benadryl. It is primarily a H1-antagonist, but also possesses an antimuscarinic effect.

dramamine.jpg


I had read the Benadryl, which is the active ingredient in most OTC sleep pills, has an idiosyncratic effect. IOW, it works for some but not others. But in the mixture sold as Dramamine it knocked me right out. But Benadryl by itself has no effect on me.

The purine compound is 8-chlorotheophylline, which is supposed to act as a stimulant to keep you from falling asleep.
 
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L-Theanine is a bit weird to me too - if I go over 100-150mg a day, it presents itself as tight neck and sore muscles. More than 300mg will cause weird not very pleasant hypomania. Lower dosage (100mg and less) seem to work as advertised (calming effect) for me. Been taking it few times a week for at least 4 years with no apparent side effects.

JacksinPA, I very much appreciate your recent contributions with drawing out the correlations between opioid acting drugs and underlining the Tyrosine structure in them! It made me think...8)
The longer I look at molecules of different psychoactives, the more I see how they are all like keys with differing groves on them, but structural similarity is amazing! :D

Look at Galantamine and how similar it is to Codeine! But look at their pharmacological profiles: Codeine is opioid receptor agonist that eventually gets converted to Morphine by our body. Galantamine primarily differs in that the amine is located one chain closer to the phenyl ring. And its pharmacology becomes an ACh inhibitor! I wonder what would happen to it if we "move" that amine a bit further and remove that methyl exposing the oxygen, as in with Morphine, would that modified Galantamine acquire opioid activity then?..

image.jpg


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Also, yesterday I've stumbled upon Opium Lettuce plant (Lactuca virosa) and it's main active alkaloids are Lactucin and Lactucopicrin. They are mainly adenosine receptor agonists and the Lactucopicrin is also ACh inhibitor.
3333.jpg

Going to perform some extraction on the plant and see how the effects are. Automatically, I think of it as an "anti-caffeine" stuff! :D
 
ad the modified galantamine, the morphine rule states that there should be 2 carbons between the amine and the tertiary carbon, no? since the structure is close to the morphinans, maybe this should be considered.
 
Thanks for the kind words.

Your proposed modification to galantamine would involve a lot of difficult chemistry. Known opioid effects can be gotten from the molecules I recently figured.

Regarding opioids, I have a paging receiver on which I hear all the EMS calls for this suburban Phila county. I heard at least 3-4 OD calls yesterday & that was from only listening for 4-5 hours. It is truly an epidemic.

I'm not familiar with the Lactuca but would be interested in hearing the results of your study. As they lack nitrogen atoms, neither one is an alkaloid.
 
Buspirone.jpg
Buspirone is a generic non-depressant anxiolytic. From the Wikipedia article:

Pharmacodynamics[edit]

[TABLE="class: wikitable floatright"]
[TR]
[TH="bgcolor: #EAECF0, align: center"]Site[/TH]
[TH="bgcolor: #EAECF0, align: center"]Ki (nM)[/TH]
[TH="bgcolor: #EAECF0, align: center"]Species[/TH]
[TH="bgcolor: #EAECF0, align: center"]Ref[/TH]
[/TR]
[TR]
[TD]5-HT1A[/TD]
[TD]3.98–214
21 (median)[/TD]
[TD]Human[/TD]
[TD][35]
[34][/TD]
[/TR]
[TR]
[TD]5-HT1B[/TD]
[TD]>100,000[/TD]
[TD]Rat[/TD]
[TD][36][/TD]
[/TR]
[TR]
[TD]5-HT1D[/TD]
[TD]22,000–42,700[/TD]
[TD]Human[/TD]
[TD][37][38][/TD]
[/TR]
[TR]
[TD]5-HT2A[/TD]
[TD]138
759–1,300[/TD]
[TD]Human
Rat[/TD]
[TD][39]
[39][36][/TD]
[/TR]
[TR]
[TD]5-HT2B[/TD]
[TD]214[/TD]
[TD]Human[/TD]
[TD][39][/TD]
[/TR]
[TR]
[TD]5-HT2C[/TD]
[TD]490
1,100–6,026[/TD]
[TD]Human
Rat/pig[/TD]
[TD][39]
[39][36][/TD]
[/TR]
[TR]
[TD]5-HT3[/TD]
[TD]>10,000[/TD]
[TD]Rat[/TD]
[TD][40][41][/TD]
[/TR]
[TR]
[TD]5-HT4[/TD]
[TD]>10,000[/TD]
[TD]Rat[/TD]
[TD][41][/TD]
[/TR]
[TR]
[TD]5-HT6[/TD]
[TD]398[/TD]
[TD]Mouse[/TD]
[TD][42][/TD]
[/TR]
[TR]
[TD]5-HT7[/TD]
[TD]375–381[/TD]
[TD]Rat[/TD]
[TD][43][44][/TD]
[/TR]
[TR]
[TD]α1[/TD]
[TD]1,000[/TD]
[TD]Rat[/TD]
[TD][36][/TD]
[/TR]
[TR]
[TD]α2[/TD]
[TD]6,000[/TD]
[TD]Rat[/TD]
[TD][45][/TD]
[/TR]
[TR]
[TD] α2A[/TD]
[TD]7.3 (1-PP)[/TD]
[TD]Human[/TD]
[TD][36][/TD]
[/TR]
[TR]
[TD]β[/TD]
[TD]8,800[/TD]
[TD]Rat[/TD]
[TD][36][/TD]
[/TR]
[TR]
[TD]D1[/TD]
[TD]33,000[/TD]
[TD]Rat[/TD]
[TD][36][/TD]
[/TR]
[TR]
[TD]D2[/TD]
[TD]484
240[/TD]
[TD]Human
Rat[/TD]
[TD][46]
[36][/TD]
[/TR]
[TR]
[TD]D3[/TD]
[TD]98[/TD]
[TD]Human[/TD]
[TD][46][/TD]
[/TR]
[TR]
[TD]D4[/TD]
[TD]29[/TD]
[TD]Human[/TD]
[TD][46][/TD]
[/TR]
[TR]
[TD]mACh[/TD]
[TD]38,000[/TD]
[TD]Rat[/TD]
[TD][36][/TD]
[/TR]
[TR]
[TD]GABAA
(BDZ)[/TD]
[TD]>100,000[/TD]
[TD]Rat[/TD]
[TD][36][/TD]
[/TR]
[TR="class: sortbottom"]
[TD="colspan: 4"]Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site.[/TD]
[/TR]
[/TABLE]
Buspirone acts as an agonist of the serotonin 5-HT1A receptor with high affinity.[4][36] It is a preferential full agonist of presynaptic 5-HT1Areceptors, which are inhibitory autoreceptors, and a partial agonist of postsynaptic 5-HT1A receptors.[4] In accordance, an animal study found that buspirone dose-dependently decreases serotonin levels in specific brain areas while increasing dopamine and norepinephrine levels.[4] It is thought that the main effects of buspirone are mediated via its interaction with the 5-HT1A receptor.[4] Some of its effects may be mediated via oxytocin release secondary to 5-HT1A receptor agonism.[47][48][non-primary source needed] Buspirone also has lower affinity for the serotonin 5-HT2A, 5-HT2B, 5-HT2C, 5-HT6, and 5-HT7 receptors.[34]
In addition to binding to serotonin receptors, buspirone is an antagonist of the dopamine D2 receptor with weak affinity.[4][36] It preferentially blocks inhibitory presynaptic D2 autoreceptors, and antagonizes postsynaptic D2 receptors only at higher doses.[4] In accordance, buspirone has been found to increase dopaminergic neurotransmission in the nigrostriatal pathway at low doses, whereas at higher doses, postsynaptic D2 receptors are blocked and antidopaminergic effects such as hypoactivity and reduced stereotypy, though notably not catalepsy, are observed in animals.[4]Buspirone has also been found to bind with much higher affinity to the dopamine D3 and D4 receptors, where it is similarly an antagonist.[46]
A major metabolite of buspirone, 1-(2-pyrimidinyl)piperazine (1-PP), occurs at higher circulating levels than buspirone itself, and is known to act as a potent α2-adrenergic receptor antagonist.[45][49][50] It may be responsible for the increased noradrenergic and dopaminergic activity observed with buspirone in animals.[49][51] In addition, 1-PP may play an important role in the antidepressant effects of buspirone.[51] Buspirone also has very weak and probably clinically unimportant affinity for the α1-adrenergic receptor.[36][52] However, buspirone has been reported to have shown "significant and selective intrinsic efficacy" at the α1-adrenergic receptor expressed in a "tissue- and species-dependent manner".[52]
Unlike benzodiazepines, buspirone does not interact with the GABAA receptor complex
 
Possibly one of the simplest opioids is fentanyl. Its chemical & structural simplicity spurred a lot of interest in so-called 'designer drugs' that would get around laws banning specific compounds. Now these molecules & variations are covered under laws banning analogs.

Fentanyl is 50-100 times more potent than morphine and up to 50 times more potent than heroin.

Fentanyl.jpg
 
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Recalling the recent discussion of the key role tyrosine (and its decarboxylated form tyramine) have in naturally occurring opioids, I looked for the derivative of fentanyl that would have a phenolic hydroxyl group in what I've labeled as the 4' position on the phenethyl group. This would give an additional receptor binding point which could influence its activity. It seems odd that this molecule has been possibly overlooked. I can't afford to look for it in Chemical Abstracts online. Anyone?

A post in 2015 by sekio stated that '4'-hydroxy fentanyl has an IC50 of 86 nM' which makes it significantly more potent than fentanyl itself, which is not surprising.

4_-_Hydroxyfentanyl.jpg
 
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AH-7921 was discovered in the U.K. in the 1970s. But I am having a hard time trying to draw an opioid receptor correlation for this molecule that would explain it being 90% as potent as morphine. See https://en.wikipedia.org/wiki/AH-7921. The 3,4-dichlorobenzamide group is obviously essential to its activity but I fail to see exactly how it would interact with a receptor.

Upjohn took the AH-7921 structure & optimized it to result in U-47700. U-47700 is apparently a RC or black market item as it was found in Prince's toxicology report.

Any guesses? These molecules act on the kappa opioid receptor.

AH-7921.jpg
 
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Upjohn had a major program running for years to optimize these opioid kappa agonist molecules. This page illustrates 2 of the later developments. For one thing, it was found that a methylene group spacer was useful & that the 3,4-dichloro substitution was not necessary for enhanced activity.

Wikipedia: U-50488 is a drug which acts as a highly selective κ-opioidagonist, but without any μ-opioidantagonist effects.[1] It has analgesic, diuretic and antitussive effects,[2] and reverses the memory impairment produced by anticholinergic drugs.[3] U-50488 was one of the first selective kappa agonists invented and research on its derivatives has led to the development of a large family of related compounds.[4][5]

U-69,593 is a drug which acts as a potent and selective κ1-opioid receptor agonist.[1][2][3] In animal studies it has been shown to produce antinociception,[1][4][5] anti-inflammation,[6] anxiolysis (at low doses),[7][8][9] respiratory depression,[5] and diuresis,[10] while having little effect on gastrointestinal motility.

The 3,4-dichloro-substituted derivative of U-69,593 is called spiradoline. Spiradoline (U-62066) is a drug which acts as a highly selective κ-opioid agonist.[1] It has analgesic,[2] diuretic[3] and antitussive effects,[4] and produces subjective effects in animals similar to those of ketazocine and alazocine.[5] The main effect in humans is sedation, along with analgesic and diuretic effects, but significant side effects such as dysphoria and hallucinations have stopped it from being used clinically.[6] Kappa-agonists have been shown to react negatively with the mu receptor[citation needed], instead of having an assumed synergy since they are both opioid receptors, such as with the mu (μ) receptors and delta (δ) receptors (which both mediate pain-relief, euphoria and overall potency of opioid effects).

Hallucinations are one thing but dysphoria is a state to stay away from: dys?pho?ri?adisˈf?rēə/
noun PSYCHIATRY



  • a state of unease or generalized dissatisfaction with life.
  • ==============================================================
Upjohn_kappa_agonists.jpg
 
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Methadone. See https://en.wikipedia.org/wiki/Methadone. From Wikipedia:

Mechanism of action[edit]

Levomethadone (the R enantiomer) is a μ-opioid receptor agonist with higher intrinsic activity than morphine, but lower affinity.[44] Dextromethadone (the S enantiomer) does not affect opioid receptors but binds to the glutamatergic NMDA (N-methyl-D-aspartate) receptor, and acts as an antagonist against glutamate. Methadone has been shown to reduce neuropathic pain in rat models, primarily through NMDA receptor antagonism. Glutamate is the primary excitatory neurotransmitter in the central nervous system. NMDA receptors have a very important role in modulating long-term excitation and memory formation. NMDA antagonists such as dextromethorphan (DXM), ketamine (a dissociative anaesthetic), tiletamine (a veterinary anaesthetic) and ibogaine (from the African tree Tabernanthe iboga) are being studied for their role in decreasing the development of tolerance to opioids and as possible for eliminating addiction/tolerance/withdrawal, possibly by disrupting memory circuitry. Acting as an NMDA antagonist may be one mechanism by which methadone decreases craving for opioids and tolerance, and has been proposed as a possible mechanism for its distinguished efficacy regarding the treatment of neuropathic pain. The dextrorotary form (dextromethadone), which acts as an NMDA receptor antagonist and is devoid of opioid activity, has been shown to produce analgesia in experimental models of chronic pain. Methadone also acted as a potent, noncompetitive α3β4neuronal nicotinic acetylcholine receptor antagonist in rat receptors, expressed in human embryonic kidney cell lines.[45]

Methadone.jpg
 
JacksinPA said:
Yes. Just do a Google search for that name. You get 4 hits but they are all pay-per-article. A couple are for glycine transporters. See
https://en.wikipedia.org/wiki/Glycine_transporter. See also https://www.nature.com/articles/nrd3893.
Click to expand...
Thanks! and sigh the paywall again, though we can 'evade' that but i try not to use that often.

So GlyT acts both as inhibitory (via GlyR binding) and excitatory (by being NMDA agonist)? That's quite strange profile (new to me)
I see similar structure of those being used to "sedate" too, aka N-benzoyl-N'-cycloalkylpiperazines
However, despite being dissimilar, the described effect are very similar to N-benzoylphthalimide, N-benzylphthalimide and N-benzoylsaccharine...
If ignoring the basicity of the "far, non-amide N" and assumes them as only H-bond donor right away, it kinda overlays well with the O in latter case. (in 3D)
 
A 'reduced' analog of methadone. This is a known compound, so apparently someone has already looked at this molecule. See https://pubchem.ncbi.nlm.nih.gov/compound/204510. Another name for this compound is given as AC1L4CPY from ABI Chem in Germany ([/FONT][/COLOR]http://www.abichem.com/). A cursory Google search turned up no additional data.

N_N_3-trimethyl-3-phenylbutan-1-amine.jpg




The meta-hydroxy derivative of AC1L4CPY should have more activity as it has an additional receptor binding point. I didn't search for this molecule.

N_N_3-trimethyl-3-phenylbutan-1-amine_m-hydroxy.jpg



The m-hydroxy derivative is also a known compound but I so far have found very little information about it. See
http://isomerdesign.com/PiHKAL/explore.php?domain=pk&id=10526

3-_4-_dimethylamino_-2-methylbutan-2-yl_phenol.jpg
 
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I took the structure of 4'-hydroxyfentanyl & applied the same minimilization technique I had use to 'reduce' methadone & arrived at 4-(2-(piperidin-1-yl)ethyl)phenol, which is another known compound that had apparently been submitted to the EPA as part of a TSCA application for a new compound (https://comptox.epa.gov/dashboard/dsstoxdb/results?search=DTXSID20293932) It would also be of interest to do an online CA search to find out who has an interest in this compound.

It would be of interest to find out if this very simple molecule has the hoped for biological activity. That would also be the case for the simpler compound without the phenol group (minimilized fentanyl).

4-_2-_piperidin-1-yl_ethyl_phenol.jpg
 
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