User:Meodipt/2011 talk archive

Phenylmorphans

Hi, I mentioned on the Opioids page that phenylmorphans may be worth including. Although none are in production an awful lot of work seems to be have done on them. I read one guys pHd thesis on-line and he specifically mentions them. A good example is J. Med. Chem. 2007, 50, 3765-3776 'Probes for Narcotic Receptor Mediated Phenomena. 34. Synthesis and Structure-Activity Relationships of a Potent í-Agonist ä-Antagonist and an Exceedingly Potent Antinociceptive in the Enantiomeric C9-Substituted 5-(3-Hydroxyphenyl)-N-phenylethylmorphan Series' - N-PE, what is the betting that 2-thienylethyl / 2-furanylethyl will prove more potent.

Thank you for all of your efforts on behalf of the Wiki community; It has made a huge difference to me. — Preceding unsigned comment added by 86.30.243.179 (talk) 22:34, 12 September 2011 (UTC)

QSAR

The book 'Opiates' by Lenz et all gives a helpful summing up of the QSAR for each class of opioid. Would it be worth adding a similar section since they are split up into similar groupings? There really needs to be a section on the phenylmorphans since there is a LOT of research on that class. On a personal note, can you point me to a database of research-name codes against manufacturer. RAM-318, RAM-320 & RAM-378 are all patented by the same people but is this the case for, say, the Ro4- prefix (Roche in this case), — Preceding unsigned comment added by 86.30.243.179 (talk) 19:57, 30 July 2011 (UTC)

Yeah I have thought about making a page about the structure-activity relationships of all the opioid ligands, but it would be a massive undertaking - potentially such a page would encompass most of the content of not just that Lenz et al book, but also the other similar reviews like the excellent ones by Daniel Lednicer and Paul Janssen, and the Casy & Parfitt book also, that are cited on various pages here. But that is a good suggestion that an individual page could be made for each of the different classes of opioids, as it seems a sensible way to split up such a vast amount of content. No doubt there would be a lot of misfit compounds left over at the end though! I'm not aware of any publicly accessible databases of manufacturer code numbers, though some more notable compounds are listed in PubChem etc of course. But most more obscure compounds are hidden in the depths of the patent literature, often without even saying which example in the patent corresponds to which code number... Meodipt (talk) 09:40, 1 August 2011 (UTC)

HU-331

I'm trying to make a page for HU-331, but when I typed it's CAS number into chemspider (or pubmed, both gave the same result) two different molecules were shown to me: http://www.chemspider.com/Chemical-Structure.112216.html & http://www.chemspider.com/Chemical-Structure.19981292.html The former looks like it could be my ticket, and the latter just confuses me.. but they both both look fairly similar to cannabidiol in structure (disregarding that floating segment on the latter). Anyway, any advise on the topic would be appreciated! Also, I got an email from chemspider thanking us for alerting them to their RCS-4 mixup, and that the page is all fixed up now. =) Thanks for your years of work toward the cause! Just let me know if I can be of any help somewhere! Enix150 (talk) 04:17, 30 January 2011 (UTC)

Definitely the first one, though I'm having trouble finding a free full text article that shows the structure. Interestingly there is an article for this compound already on the Catalan language wikipedia of all places, which should have some useful content if you can find an autotranslate service that includes Catalan!! Meodipt (talk) 06:20, 30 January 2011 (UTC)

Used a translator first, but the result wasn't exactly something wiki-worthy.. So I did it by hand, but some of the phrases are still a little iffy. As for chemspider, I now believe it was sorted improperly because they had it filed under an incorrect SMILES code. I'm beginning to worry that I should be editing there too! Enix150 (talk) 22:20, 30 January 2011 (UTC)

That looks really good actually, might clean up some of the wording and perhaps draw a nicer image for it when I get time, but you've made an excellent start  :-) Meodipt (talk) 02:51, 31 January 2011 (UTC)

JWH-018

Hey Meodipt, do you think you could take a look at the toxicity section] of JWH-018. An IP has removed part of it twice today and I just want to check it is correct before reverting again. The papers here at bluelight may be of use. Thanks SmartSE (talk) 20:42, 7 February 2011 (UTC)

It is probably correct but I'm not sure if it is supported by reliable sources? Certainly there have been cases reported of convulsions following use of JWH-018 but I haven't seen any serious examination of this in the scientific literature as yet. These reports seem almost entirely limited to JWH-018 in particular as I have not seen any comparable reports of convulsions occurring with other related compounds (even with more potent varients like JWH-210 or AM-2201), or with other potent CB₁ full agonists like HU-210 (though this may just be due to the much larger volumes of JWH-018 sold and consumed compared to other synthetic cannabinoid drugs). Also it is unclear whether this is a strictly cannabinoid receptor mediated effect, especially as the reports of convulsions don't seem to show a clear dose response relationship (i.e. most case reports concerning large overdoses of JWH-018 didn't result in convulsions, yet in some cases convulsions were reported even after small doses). I've seen it suggested that perhaps these are idiosyncratic reactions by people with a specific sensitivity to JWH-018, or that they may be due to off target effects like GABA antagonist or glutamate agonist action - after all most of these cannabinoid compounds have barely been screened at other targets and no one knows what else they may be doing besides acting as cannabinoid agonists. As for the possible carcinogenic effects, JWH-018 has been shown to form epoxides on metabolism but there is no evidence to show whether or not these are carcinogenic (not all epoxides are) - though even if JWH-018 itself is not carcinogenic, the pyrolysis fragments from any naphthalene containing compound seem unlikely to be very healthy! So basically the toxicity section is mainly anecdote and speculation at this stage, supported by references that show it is probably true but do not prove it. Certainly the toxicity section is important and appropriate for wikipedia to cover, but the absence of reliable sources is a problem. Meodipt (talk) 06:24, 8 February 2011 (UTC)

Thanks for your reply, someone has again removed it, but explained in the edit summary why. I've got a copy of the only metabolism paper so will try and get that written up later on today and see if I can find someone to draw a picture of the proposed metabolites. As is coming customary, I guess it is still a case of "wait and see". I guess you can tell I'm not a pharamacologist - but how difficult can it be to find an LD50 in rats? SmartSE (talk) 10:44, 8 February 2011 (UTC)

Oh running an LD50 in rats isn't that difficult or expensive, indeed one of the Chinese bulk manufacturers apparently did a preliminary toxicity screen in rats for JWH-018, as part of their risk assessment process before they agreed to start producing it. However since this was not published in a peer reviewed journal there is no way of knowing if it can be trusted, and it is not a reliable source as far as wikipedia is concerned (though it was cited as a reference on the page until the more acceptable papers by Maurer HH et al were published). Besides the LD50 in rats is a crude measure, which is of little help when trying to find the cause of non-fatal but serious adverse effects in humans (like convulsions). It may be years before long-term studies have been done to definitively prove or disprove whether JWH-018 and similar naphthoylindole compounds are carcinogenic or not - after all these long term carcinogenicity studies are by far the most expensive part of the normal pre-clinical drug development process, but in this entirely unregulated industry there is no need for either manufacturers of the active ingredients, or marketers of the final "synthetic cannabis" blends, to fund such studies before selling the compounds to the public. While governments for their part are mainly interested in just banning the compounds outright rather than carrying out an extensive evidence based risk assessment on which regulation could be based, and designer drugs can be banned without having to spend huge amounts on studies to prove they are carcinogenic. Showing that a compound has abuse potential is generally enough for this, and for JWH-018 at least there are already sufficient case reports in the literature to show this, so there is enough evidence to ban it without having to fund further research to assess its other possible harms. Meodipt (talk) 23:39, 8 February 2011 (UTC)

Ok thanks again for the info. I just noticed there is a new legal high being called A3A [1] [2] which by all accounts (from unreliable sources) is 1,5-Methano-1H-3-benzazepine,2,3,4,5-tetrahydro-, hydrochloride there are a couple of papers [3] [4] about it but I can't access them. Any chance of knocking up a quick stub? (Why the media continue to advertise these is beyond me... ) SmartSE (talk) 13:00, 10 February 2011 (UTC)

The chemical name they are advertising as "A3A" is a known compound, a nicotinic agonist related to varenicline. It seems most unlikely that this is the same compound as whatever they are selling, given the completely different reported effects. I don't think these need wiki pages as the compounds being sold under these names do not match the known pharmacology of those compounds. See also Corey lactone 4-phenylbenzoate...Meodipt (talk) 06:39, 11 February 2011 (UTC)

I hope I'm not intruding, but should we not redirect them instead to what is actually being sold in A3A? If the composition is known, that is. Like with the Eric-4 article being a redirect to RCS-4. On another note, the compound that SmartSE described looks like varenicline except that it lacks the pyrazine ring, but it is still a nicotinic acetylcholine receptor agonist. That couldn't actually be what is being sold, could it? Enix150 (talk) 11:27, 15 February 2011 (UTC)

Thats the point, as with the supposed "corey lactone 4-phenylbenzoate" the actual ingredients of what is being sold as "A3A" appear to be completely unknown, there are no good analyses that I've heard of. I doubt it even contains the nicotinic agonist compound they say it is, unless they mixed that with a dopaminergic stimulant in the hope of finding a blend that would be really addictive! But even in that case an analogue of an anti-smoking drug like varenicline would seem an odd choice... Meodipt (talk) 12:04, 16 February 2011 (UTC)

Arenobufagin

Hi Meodipt. Your structure does not look nice around the oxygen in the upper right corner. Could you upload a new version to Commons? --Leyo 00:09, 8 March 2011 (UTC)

Hey Meodipt

Just wanted to say I saw a certain something in the news the other day and wanted to congratulate you. Nice work! el3ctr0nika (Talk | Contribs) 00:14, 18 May 2011 (UTC)

Cheers man  :-) Meodipt (talk) 11:32, 18 May 2011 (UTC)

Proposed Image Deletion

A deletion discussion has just been created at Category talk:Unclassified Chemical Structures, which may involve one or more orphaned chemical structures, that has you user name in the upload history. Please feel free to add your comments.  Ronhjones  ^(Talk) 22:58, 10 June 2011 (UTC)

OHMEfentanyl

Hi, I note you edit a lot of the sections concerning drugs acting on the CNS. I noticed that OHMEfentanyl is commonly cited as the most potent MOR known to man BUT if you look at Current Medicinal Chemistry Aug 1997 page 257, entry 6d describes the activity of the 4-COCH2CH3 analog of OHMEfentanyl. ED50 is 0.0001mg/kg (OHMEfentanyl is 0.00017mg/kg) & the activity is given as x30000 morphine (OHMEFentanyl is x25000). Racemic thioOHMEfentanyl is also described as being around 20% more potent than racemic OHMEfentanyl.

Going out on a limb, the 2-furanyl analogs of fentanyl (synthesized by BOC in the 1970s) were around x3 the potency of the phenyl analog. This pattern (2-furanyl>2-thienyl>phenyl) is seen across a range of other MOR agonists.

I've been adding patent references to a lot of opioids, I notice your cleaning them up so thanks! — Preceding unsigned comment added by 86.30.243.179 (talk) 14:12, 12 July 2011 (UTC)

Yes, there are I think at least 5 analogues or derivatives of ohmefentanyl or carfentanil that are more potent than ohmefentanyl itself, as you say most of them are listed in that 1997 Current Medicinal Chemistry paper (ref 4 on the OMF page). However when you get up to these kind of potency levels it is difficult to accurately assess how strong they are exactly, I've seen values anywhere between 18,000x - 30,000x morphine cited, and unless they are compared directly under identical assay conditions then it is also very difficult to rank them and say which is the strongest. Anyway the question is largely academic, once the binding affinity goes this high then usually either efficacy drops and partial agonists or antagonists start to be produced instead, or if they are still full agonists (as with most of these super-potent fentanyl derivatives) then they cause receptor desensitization, internalisation and downregulation so fast, that they practically act as antagonists anyway after the first couple of doses, because the tachyphylaxis is so extreme. Meodipt (talk) 00:50, 13 July 2011 (UTC)

JTE 7-31

Hey Meopdipt, I noticed that you added JTE 7-31 to the cannabinoid template. I was wondering if you could tell me more about it or whether it is related to the CB₂ inverse agonist JTE-907. Even a source would help; I just haven't found much information in my searches so far. Thanks! Enix150 (talk) 20:16, 12 September 2011 (UTC)

Hi there. Yeah the JTE 7-31 was invented by Japan Tobacco, same as JTE-907, and pretty sure they are both claimed in the same patent, WO 1997 29079. It is a selective CB₂ agonist but still with appreciable activity at CB₁, with a K_i of 0.088nM at CB₂ vs 11nM at CB₁. So the pharmacological profile would be quite similar to something like A-834,735 most likely, though with somewhat higher CB₂ selectivity. Reason I added it to the template was because I came across it mentioned in a review of CB₂ agonists one day and reckoned that it was obviously notable enough for its own page when I got around to writing one, but unfortunately I now can't remember which review paper that was, out of my large and somewhat disorganised collection. So it will have to wait until I find the paper again, unless someone else makes a page for it in the meantime. I'm sure I found it on PubChem before but the search doesn't seem to be working right now, the SMILES code is Oc3ccc(cc3)CCN(C1=O)Cc(c2NCCCCC)c1ccc2OC anyway Meodipt (talk) 10:32, 14 September 2011 (UTC)

Ah yes here is is, 2-[2-(4-hydroxyphenyl)ethyl]-5-methoxy-4-(pentylamino)-3H-isoindol-1-one [5] Meodipt (talk) 08:05, 16 September 2011 (UTC)

I found a patent describing its synthesis and a binding assay, US 6017919, but I still haven't been able to find any papers mentioning it. You wouldn't want to share some of your collection, would you? Hope that's not too forward! I have a collection of my own to trade, but I doubt it compares. Also, I usually just upload most of mine online anyway so you could just google search the paper names. Enix150 (talk) 14:17, 30 September 2011 (UTC)

Well I wouldn't want to share my document collection beyond the terms of the copyright, the publishers might not be impressed. Most of the more relevant and interesting papers are listed on here as references for one article or another - though not the elusive one with the binding data for JTE 7-31 of course, why did I not write it down at the time! Do you have an email address? Meodipt (talk) 01:51, 1 October 2011 (UTC)

Yes that is perfectly understandable; any contributions will be respected and greatly appreciated! My email is enix150@yahoo.com hope to hear from you soon. :-) Enix150 (talk) 18:18, 2 October 2011 (UTC)

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Ur-12

Since you seem to have an interest and experience in this area, could you please take a look at the new article Ur-12. Is it notable? -- Ed (Edgar181) 19:45, 26 October 2011 (UTC)

The original author requested deletion per WP:CSD#G7 today but as you have made edits to it, it was declined. If you don't think it belongs, then I'm happy to press the buttons if you agree. SmartSE (talk) 11:41, 30 October 2011 (UTC)

Well the reason given for deletion is incorrect, as the substance certainly does exist and has been described in the literature. As for notability, I think this pair of compounds are a nice example of indole-3-carboxamides other than those ones from the Org series, and the related indolopyridones from the same paper have been mentioned in a couple of secondary sources, one of which even discussed these two compounds specifically. I'd have no problem with the page staying up, the only problem is the name - UR-12 has not been mentioned anywhere else and seems to be an invented code by someone trying to sell the stuff, but the actual chemical name is far too long and unwieldy for a page name. Meodipt (talk) 18:25, 30 October 2011 (UTC)

evidence not presented176.51.76.148 (talk) 07:40, 31 October 2011 (UTC)

(what?!) Yeah I agree that the name is difficult, 7-methoxy-1-(2-morpholinoethyl)-N-((1S,2S,4R)-1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl)-1H-indole-3-carboxamide doesn't really trip off the tongue. I know that it isn't great, but how about C26H37N3O3? {{displaytitle}} can be used to subscript the numbers so that it looks like the formula in the title. SmartSE (talk) 10:20, 31 October 2011 (UTC)

Found a few more relevant references, two of which refer specifically to these compounds - although it is clearly the 2-methyl derivative that is the more notable. Also noticed that the chemical name contains forbidden characters (i.e. square brackets) so not sure what to do about that, as if the page is kept, its not accurate to leave the name as a made up code number like "UR-12"... Meodipt (talk) 10:23, 31 October 2011 (UTC)

The display title template can deal with any characters I think so the square brackets wouldn't be a problem, but is there a more generic name we could use instead of the full one? If not, then I'm inclined to move it to C26H37N3O3 for the moment, as that is at least better than something completely made up. SmartSE (talk) 10:32, 31 October 2011 (UTC)

Well the shortest correct name would be something like N-(S)-Fenchyl-1-(2-morpholinoethyl)-7-methoxyindole-3-carboxamide which is not too ugly a pagename...however I wonder if for notability's sake it would be better to make the page about the 2-methyl derivative instead, which would make it a bit longer. Meodipt (talk) 10:41, 31 October 2011 (UTC)

ODT

I need to speak to you privately before you restore your edit. I am a place holder (talk) 05:42, 14 December 2011 (UTC)

If you wish to speak privately then give me an email address. But I think it is highly notable that the surreptitious addition of ODT to kratom resulted in the deaths of at least nine people in Sweden alone in just one year - this is clearly something the public need to be warned about, especially seeing as I can't find a single case of fatal overdose from kratom alone. This has massive potential to influence the risk assessment done of kratom and hence its scheduling status by governments worldwide, it is important people know that the brand name commercial products may contain undeclared full opioid agonists and could result in death even when not mixed with other sedatives, unlike genuine unadulterated kratom leaf. Indeed its probably worth adding a note about this to the kratom page too. Meodipt (talk) 08:56, 14 December 2011 (UTC)