Ketamine salts solubility

[thegreenhand]

I'm pretty sure this statement is bullshit. Plenty of drugs target membrane proteins, like maybe even a majority of them.

Yeah I have trouble believing that too. Hence, why I asked about LSD. I had to make sure my entire conception of pharmacology wasn’t wrong lmao

 

[Nagelfar]

I'm pretty sure this statement is bullshit. Plenty of drugs target membrane proteins, like maybe even a majority of them.

It clearly states as much, it's talking about previously unassailable ones:

Indeed, membrane proteins account for over 60% of the targets of all FDA-approved small-molecule drugs.

 

[thegreenhand]

It clearly states as much, it's talking about previously unassailable ones:

Yep definitely missed that line, my bad

 

[Skorpio]

It clearly states as much, it's talking about previously unassailable ones:

Then where is the proof of concept of targeting a receptor that has evaded ligand design previously? Folate receptor, carbonic anhydrase, and epidermal growth factor receptor have ligands, do they not?

 

[Nagelfar]

Moreover, membrane proteins are also difficult to study in an isolated form, as they tend to lose essential cellular feature and may be deactivated.

↑in search for new novel ligands for drugs, a lot of in vitro techniques have to be used to isolate: this appears to allow tagging for improved in vivo study or to locate where the site of a receptor is that evades in vitro conditions by becoming inactive during that process.

Any drug whatsoever that has had a hurdle in it's development due to reasons of isolating the target for study when scrutinized fall under this criteria.

 

[S.J.B.]

4-Aryl-1-oxa-4,9-diazaspiro[5.5]undecane Derivatives as Dual μ-Opioid Receptor Agonists and σ1 Receptor Antagonists for the Treatment of Pain
Corresponding author: Carmen Almansa (Drug Discovery and Preclinical Development, ESTEVE Pharmaceuticals SA, Barcelona, Spain)
Journal of Medicinal Chemistry 2020, Volume 63, Issue 5, Pages 2434–2454
Published online November 19th, 2019
https://doi.org/10.1021/acs.jmedchem.9b01256

The synthesis and pharmacological activity of a new series of 1-oxa-4,9-diazaspiro[5.5]undecane derivatives as potent dual ligands for the sigma-1 receptor (σ1R) and the μ-opioid receptor (MOR) are reported. The different positions of the central scaffold, designed using a merging strategy of both target pharmacophores, were explored using a versatile synthetic approach. Phenethyl derivatives in position 9, substituted pyridyl moieties in position 4 and small alkyl groups in position 2 provided the best profiles. One of the best compounds, 15au, showed a balanced dual profile (i.e., MOR agonism and sigma antagonism) and a potent analgesic activity, comparable to the MOR agonist oxycodone in the paw pressure test in mice. Contrary to oxycodone, as expected from the addition of σ1R antagonism, 15au showed local, peripheral activity in this test, which was reversed by the σ1R agonist PRE-084. At equianalgesic doses, 15au showed less constipation than oxycodone, providing evidence that dual MOR agonism and σ1R antagonism may be a useful strategy for obtaining potent and safer analgesics.

 

[S.J.B.]

Discovery of EST73502, a Dual μ-Opioid Receptor Agonist and σ1 Receptor Antagonist Clinical Candidate for the Treatment of Pain
Corresponding author: Carmen Almansa (ESTEVE Pharmaceuticals S.A., Barcelona, Spain)
Journal of Medicinal Chemistry 2020, Volume 63, Issue 24, Pages 15508–15526
Published online October 16th, 2020
https://doi.org/10.1021/acs.jmedchem.0c01127

The synthesis and pharmacological activity of a new series of 4-alkyl-1-oxa-4,9-diazaspiro[5.5]undecane derivatives as potent dual ligands for the σ1 receptor (σ1R) and the μ-opioid receptor (MOR) are reported. A lead optimization program over the initial 4-aryl analogues provided 4-alkyl derivatives with the desired functionality and good selectivity and ADME profiles. Compound 14u (EST73502) showed MOR agonism and σ1R antagonism and a potent analgesic activity, comparable to the MOR agonist oxycodone in animal models of acute and chronic pain after single and repeated administration. Contrary to oxycodone, 14u produces analgesic activity with reduced opioid-induced relevant adverse events, like intestinal transit inhibition and naloxone-precipitated behavioral signs of opiate withdrawal. These results provide evidence that dual MOR agonism and σ1R antagonism may be a useful strategy for obtaining potent and safer analgesics and were the basis for the selection of 14u as a clinical candidate for the treatment of pain.

 

[Nagelfar]

↑it is always interesting to have a contender for opioid activity with possible diminished (precipitated) withdrawal.

Curious though what is meant by:

…Contrary to oxycodone, as expected from the addition of σ1R antagonism, 15au showed local, peripheral activity in this test…

Are we meaning the opioid is functioning like a local anesthetic? I can't see that being the case as the receptors are central-nervous (perhaps somehow displayed with regard to the point of pain on the body?) but I am ignorant of how the terminology would be otherwise meant in this context.

 

[sekio]

this thread suxamethonium chloride

 

[sekio]

low opioid withdrawal? pull the other one it has bells on it

and Nagelfar - did you know that intravenous lidocaine is apparently used as a systemic painkiller? I guess the sodium channels don't care where the lidocaine comes from...

 

[Nagelfar]

↑wow, wouldn't think that would be a first line of approach in most cases due to the cardiotoxicity of a full topical anesthetic rapidly reaching the heart by those means.

I just didn't see how the reverse would be true, and opioids used a local a painkiller.

 

[Rectify]

2-METHYLAMINOSAFROLE
1-(1,3-benzodioxole-5-yl)-2-methylaminopropane

My Drugs Are Precious.

You're probably a zombie. :D

 

[Nagelfar]

Source: © Royal Society of Chemistry
“The aromatic cluster consists of 12 bismuth atoms (purple) around a central thorium atom (blue)”
Heavy-metal cluster sets size record for metal aromaticity — By Katrina Krämer – 4th January 2021

I am always interested in new aromatic structures and possible starting points for organometallic chemistry, now this certainly isn't organic, but putting so many metal atoms together in something non-planar with so few shared electrons is quite something.

It has this octahedron-tetrahedron, solid swing set type structure I find interesting:

A 12-membered bismuth ring has become the biggest Hückel aromatic molecule made purely from metal atoms.¹ Despite having only two π electrons, the compound’s ring current – an indicator of aromaticity – is similar to that of porphine with its 26 π-electrons.

Since the discovery of aromaticity in the 19th century, it has been a property mostly reserved for carbon compounds with the occasional heteroatom. In 2001, chemists reported the first all-metal aromatic compound, a four-aluminium ring.² Over the years, more examples of π-aromatic clusters have emerged, though none of them containing more than five metal atoms.

‘Our compound is a new milestone, as the system is much larger,’ says Stefanie Dehnen from the University of Marburg in Germany. Together with her colleague Florian Weigend, she led a team that has made an anionic 12-bismuth ring stabilised by a central thorium cation. It is the biggest all-metal molecule that is aromatic according to Hückel’s 4n+2 rule.

A diagram of the bismuth cluster's molecular structure from two angles

Source: © Eulenstein et al/Nat. Chem. (2020)

Molecular structure of the [Th@Bi12]4− cluster anion from the top and the side

‘Although it’s difficult to quantify, we call its aromaticity “substantial” because only two [π] electrons do the job of creating a huge ring current, which before has not [been] seen,’ Dehnen says. The ring current is twice as strong as in benzene and similar to what is seen in porphine, a 26 π-electron compound.

Unusual about the molecule is not just its size, it’s also that it isn’t planar – apparently violating one of Hückel’s criteria for aromaticity. ‘We interpreted this planarity argument more into the direction of symmetry,’ explains Dehnen. ‘It’s a very symmetric compound, and although the ring is not planar – it’s more like a doughnut in which the ring current occurs – it’s very similar to the one that you find in benzene.’

The team took great care to verify the molecule’s aromaticity, calculating its ring current and nucleus-independent chemical shift using every kind of computational method in the book. ‘Luckily, the quantity in the end was always more or less the same – so we are really very sure about the large ring current,’ says Weigend. The reason this was so important, notes Dehnen, is that ‘there are a lot of papers in the literature that define everything that is somehow not localisable as aromatic, including the typical property of metal clusters as having cluster orbitals.’

An image showing the ring current in the bismuth cluster, symbolised by an orange (high current density) hexagon with a green (low current density) centre
Source: © Eulenstein et al/Nat. Chem. (2020)

The torus-shaped current density is similar to that in planar rings, despite the perpendicularly oriented bismuth atoms

‘I think [with this molecule] metal aromaticity has expanded to macrocyclic aromaticity,’ says Miquel Solà who works on catalysis and aromaticity at the University of Girona in Spain. The cluster is also surprisingly stable, he says, existing both as a solid and in solution. ‘Most [all-metal aromatics] you cannot have in a bottle.’ Many have never been isolated, existing only in the gas phase, or can only be stabilised by an array of bulky ligands.

Dehnen hopes that the findings serve as an inspiration, ‘that you should never stop with things that you know’. Uncommon compounds such as this one can serve as molecular models of metal alloys and could even be used as catalysts. The Marburg team is now examining whether the cluster shows reactivity typical for aromatics, for example susceptibility to electrophilic substitution.

References
¹ A R Eulenstein et al, Nat. Chem., 2020, DOI: 10.1038/s41557-020-00592-z

² X Li et al, Science, 2001, 291, 859 (DOI: 10.1126/science.291.5505.859)

 

[Rectify]

HEYZEUS
(2S)-1-(2-methylaminopropyl)-piperidine

SKANDA
1-(2-aminopropyl)-2-oxo-4-pentyl-piperidine

SPARKLE_LEE
6-chloro-5-methoxy-2-aminoindan

NICE
N-(1-methyl-2-phenylethyl)-2-amino-5,6-methylenedioxyindan

SASSY (really very nice?)
N-(1-methyl-2-(3,4-methylenedioxyphenyl)ethyl)-2-amino-5,6-methylenedioxyindan

SHIMMERING
1-(3-methoxy-4-chlorophenyl)-2-ethylaminopropane

 

[Rectify]

BRASS MONKEY
(1R,2R)-1-(2-oxo-3-oxapentyl)-3-oxo-4-oxa-2-((2Z)-2-pentenyl)cyclopentane

Possibly an intoxicating libation based on gbl and ethyl jasmonate.

Or, perhaps--like me--it just smells good.

 

[polymath]

Some old article in Rhodium's drug chemistry archive described a tryptophan decarboxylation reaction where the amino acid is heated in biphenyl under a nitrogen atmosphere. The biphenyl is just meant to function as something unreactive with a very high boiling point. Would methylsulfonylmethane also be a suitable medium for this? Its boiling point is near 250 degrees Celsius and shouldn't be very reactive either.

 

[Rectify]

SHANE
1-(2-bromophenyl)-2-aminopropane

 

[Rectify]

MMDA
1-(4,5-methylenedioxy-3-methoxyphenyl)-2-aminopropane

from The Wacker Oxidation of Fractionally Distilled Nutmeg Oil, then ammonation.

 

[Rectify]

 

[sekio]

it's worth a try, is this not the same reaction that can be run in spearmint oil (menthone acting as a catalyst of sorts) ?