⫸STICKY⫷ Useful neuroscience/pharmacology threads

[AlsoTapered]

Library Genesis

libgen.rocks

Analgesics From Chemistry and Pharmacology to Clinical Application

Another must have tome.

 

[mr peabody]

Albert Hofmann and colleagues

PSYCHEDELIC MEDICINE | PHARMACOLOGY - 80 articles

PHARMACOLOGY | +80 articles

Psychedelic Pharmacology by James Kent Most psychedelic molecules are structurally similar to neurotransmitters that modulate signal flow in the brain. If we take a close look at the structure of common neurotransmitters, the transmitters most closely related to the classic psychedelics...

bluelight.org

 

[mr peabody]

PSYCHEDELIC MEDICINE | NEUROSCIENCE - 80 articles

NEUROSCIENCE | +80 articles

Alexander Shulgin An Introduction to Psychedelic Neuroscience Tanya Calvey, Fleur Margaret Howells | January 2018 This chapter is an introduction to the volume Psychedelic Neuroscience of Elsevier's Progress in Brain Research addressing the neurobiological mechanisms of psychedelic drugs, the...

bluelight.org

 

[AlsoTapered]

UNODC - Bulletin on Narcotics - 1958 Issue 4 - 006

Braenden, Eddy & Halbach (1955), summarizing the relationship between chemical structure and analgesic action, said "In morphine and its derivatives the methyl substituent on nitrogen seems essential because its substitution by other alkyl groups reduces or abolishes analgesic action." It is...

www.unodc.org

Scroll down to the scanned images - these are levorphanol homologues with a variety of N-substituents. The second image lists:

Ro 4-1539 - ED50 0.010 (0.009-0.012) mg/kg

i.e. some x480 morphine in potency.

Ro4-1539 - Wikipedia

en.wikipedia.org

Now, their is a simply huge number of antagonists and partial agonists that may be N-dealkylated using non-classical Polonovski reactions (and other methodologies).

N-Dealkylation of Amines

N-dealkylation, the removal of an N-alkyl group from an amine, is an important chemical transformation which provides routes for the synthesis of a wide range of pharmaceuticals, agrochemicals, bulk and fine chemicals. N-dealkylation of amines is also ...

www.ncbi.nlm.nih.gov

One example would be the N-dealkylation of nalmefene. The N-methyl homologue of nalmefene is some x60 morphine* and so, based on known QSAR data, the N-2-(furan-2-yl)ethyl homologue (like Ro 4-1539) should be around x1600 morphine in potency.

*'Opiates' 1986 by Lenz et all: Page 63 'Structure-Activity Relation of Morphine and Related Structures' Table 3.3

Thus NALMEFENE represents a pre-precursor (2 steps) to:

17-(2-(futan-2-yl)ethyl)-4,5α-epoxy-6-methylenemorphinan-3,14-diol

1 hosted at ImgBB

Image 1 hosted in ImgBB

ibb.co

Later work by Professor Helmut Schmidhammer at the University of Innsbruck in the mid-1990s demonstrated that replacing the 14-hydroxy moiety for a 14-methoxy (such as 14-methoxy metopon) increased analgesic activity by almost 2 orders of magnitude. It is believed that this is a result of increased affinity for the DOR.

14-Methoxymetopon - Wikipedia

en.wikipedia.org

So while the QSAR has not been funny explored, it's possible that:

17-(2-(futan-2-yl)ethyl)-4,5α-epoxy-6-methylenemorphinan-14-methoxy-3-hydroxyl

Demonstrates even higher activity but careful examination of his would would be required. But, if it proved to be the case that this compound could in fact be over 100,000 times the activity of morphine. But I would consider a compound with such activity to be a chemical weapon first and foremost:

1 hosted at ImgBB

Image 1 hosted in ImgBB

ibb.co

I should add that a Canadian BLer has already found reference to a compounds that is estimated to be over 100,000x morphine it it's analgesic activity, likely due to possessing both MOR and DOR activity so the above does not represent a range of activity unknown to science.

 

[AlsoTapered]

(1R,5S)-9-methoxy-9-phenyl-3-(2-phenylethyl)-3-azabicyclo[3.3.1]nonane

(1R,5S)-9-methoxy-9-phenyl-3-(2-phenylethyl)-3-azabicyclo[3.3.1]nonane | C23H29NO | CID 21151698 - structure, chemical names, physical and chemical properties, classification, patents, literature, biological activities, safety/hazards/toxicity information, supplier lists, and more.

pubchem.ncbi.nlm.nih.gov

BTW the above compound is an example of an opioid demonstrated to be over x100,000 morphine in potency.

If one has access to ChemOffice, it's worth overlaying the above compound with fentanyl, BDPC and similar compounds. The above compound hasn't seen optimization such as replacing the beta-aromatic with a 2-thienyl or 2-furanyl moiety or the addition of a chiral beta-hydroxy moiety.

But in a PM the Canadian BLer noted that researchers used OHMEfentanyl as a reference compound and were shocked to discover that even after 3 applications of OHMEfentanyl, the compound was not dislodged from the MOR receptors.

When we reach these levels of potency, Ki values are not measured in micromoles (uM) but rather in nanomoles (nM). I have mistakenly read affinity data ASSUMING the values were in uM only to discover upon closer examination that the values were in nMs.

The paper 'A MOR Antagonist with High Potency and Antagonist Efficacy among Diastereomeric C9-Alkyl-Substituted N-Phenethyl-5-(3-hydroxy)phenylmorphans'

Although the above paper ostensibly discusses antagonist, it's important to note that opiate ligands which display antagonist activity MUST include a meta-hydroxy moiety on the alpha aromatic (benzene) ring or bioisostere thereof.

 

[vecktor]

^ not a new compound at all. However the potency in vivo is nowhere near as high as is suggested by in vitro. ED50 32ug/kg in guinea pigs. In humans it is not that potent (fentanyl level potency)
Patent is 1972 to Sanko company, Chem Pharm Bull (Japan) 2050-2057 (1970)

I don't understannd this obsession with in vitro potency over everything, are you playing some kind of smackhead top trumps?

Safer opioids would be a good thing and super potent /= safer
Dezocine based compounds with reduced respiratory depression and or ceiling effect would be a better approach if harm reduction really was your priority

 

[AlsoTapered]

Library Genesis

libgen.pm

Above is a hotlink to the paper that discusses Spiridone (R-4066) and it's derivatives.
From the lext:

A comparison of the potency ratios (Table 11), computed relative to methadone, shows that the racemic mixtures of compounds lb and IC are half as potent (ratio = 106) as compound la (ratio = 212) which possesses to chiral center. This may indicate the existence of only one activeste sreoisomer as has been shown in the methadone-methadol-acetylmethadol series[8]. The relative potencies were la > lb = Ic
So it's x212 more potent than methadone and it's duration of action is over three times that of methadone.

Library Genesis

libgen.pm

[8] Above is the link that discusses how the ketone, hydroxyl or ester moiety interacts with the amine function present within the 3,3-diphenyl heptanone (methadone) class of opioid.

Now, it one overlays despropanyl bezitramide (bezitramide is a prodrug), you instantly see that the 3 aromatic rings overlay, the basic amine overlays and the nitrile overlays the ketone function so while the two classes of opioid appear unrelated, in truth when viewed in 3D in their minimum-energy conformation, they overlay.

It also suggests that their is a despropanyl bezitramide derivative that is much MORE potent than the parent compound.

 

[MedicinalUser247]

Wow ! This is a ton of valuable information.

 

[someguyontheinternet]

If you're interested in learning neuropharm I would highly recommend learning basic neuroscience first, including major brain regions and structures to understand the flow of information inputs as well as how behaviors are produced and what regions are involved in higher order processing, memory, and attentional awareness. Then learn pharmacology with the perspective of thinking about neuronal circuits

 

[MedicinalUser247]

See that's the thing... I've studied a little bit about Pharmacology, but not so much about chemistry and neuroscience.

 

[someguyontheinternet]

Having chemistry knowledge does help with pharmacology but its more necessary in medicinal chemistry. In medicinal chemistry usually you already have a protein target you're trying to drug and designing a chemical to do that. Neuropharm is more about finding the target in the first place

 

[AlsoTapered]

Having chemistry knowledge does help with pharmacology but its more necessary in medicinal chemistry. In medicinal chemistry usually you already have a protein target you're trying to drug and designing a chemical to do that. Neuropharm is more about finding the target in the first place

I studied medicinal chemistry for 8 years and practiced that learning for decades. When I studied, neuropharmacology didn't really exist as a separate subject.

I'm happy for people to give me targets and then going on to design ligands. Often it's training-sets that discover targets.

 

[someguyontheinternet]

What do you mean by training sets?

What I mean by discover targets is to elucidate the underlying mechanism of a signaling pathway or neuronal circuit, I didn't think that medicinal chemists were involved in that part

 

[AlsoTapered]

I have posted a link to papers that use training-sets in this thread. I was used to find the key moieties and their spatial relationships for MOP, DOP and KOP ligands. Now those appear to use the minimum-energy conformation but new software allows for near-minimum conformations.

 

[someguyontheinternet]

Ah you're referring to ligands as targets, I'm using target to refer to a protein/receptor. Maybe I need to find the correct terminology

 

[AlsoTapered]

Ah you're referring to ligands as targets, I'm using target to refer to a protein/receptor. Maybe I need to find the correct terminology

No - a ligand is a chemical which has affinity for a receptor. I'm not sure if the term 'target' and 'receptor' refer to quite the same thing. I'm GUESSING that 'target' more generally refers to a domain - but when I studied, we targeted receptors using ligands to produce agonism, partial-agonism, silent agonism, inverse agonism or antagonism. But language changes and can mean different things in different disciplines.

 

[someguyontheinternet]

How do you find which receptor/protein to target?

 

[AlsoTapered]

Well, historically it was the study of naturally occurring ligands but over time rational design and high-throughput screening have taken over. More recently people began to use in-silico models and in the last few months... sigh... AI.

But if you pulled those papers, you can see how we first classified an 'opiate receptor' and then discovered MOR, DOR and KOR were subtypes and most recently NOP has been identified. Now some researchers theorize that their are several more subtypes but it's that theorizing isn't what I deal with,

 

[someguyontheinternet]

In my recent courses we've been taught that the process used to be based on action of natural products but it has shifted to elucidation of disease associated signaling pathways, crystalization of proteins, and rational computer aided design based on crystal structure

 

[AlsoTapered]

Well that's interesting - approaching the problem from the opposite direction. I cannot speak for proteins (although I read they are 'self organizing') but with small-molecule drug design, it's been recognized that binding may not occur in the minimum-energy conformation so now near-minimum conformations are covered by in-silico training-sets.

A good example would be the first synthetic opioid - pethidine (Demerol). Now the piperidine ring can adopt either boat or chair conformation but it's been shown that the hydrogen-bond between the O of the ester and the N are key to binding. That's why I linked to that paper on Spiridone (or specifically, the link to the paper referenced in the paper covering them.

People always seem to think such compounds are essentially flat and exist in that 2D form. But when you realize that the ketone moiety actually bends over the 3,3-diphenyl motif, you realize the active conformation is UTTERLY unlike those pictures which are simply used as a diagram rather than a map.

Another one I recall from early in my education was HOW psilocin could be orally active. How does it cross the BBB. Well it turns out that the tryptamine chain bends back over the indole and the 4-OH and N form a hydrogen-bond.

But truly - while crystalline forms of proteins had been used to elucidate structure via X-ray crystallography, I don't think many people were using such data to find targets.

But natural-->rational design-->high throughput screening-->in-silico and AI were the technologies employed for small-molecule drug design. Most drugs are still small-molecule but their ARE some powerful new techniques.