Talk:Brorphine

Unsupported claim about hERG affinity and questionable claim about biased agonism

As far as I can tell, the claim of brorphine inhibiting the hERG channel is entirely bogus. The study on biased agonism may be valid, but it would seem to contradict all other information on the topic. Post a citation if you can find it; if none comes to light I will remove the claim. Towelbin (talk) 02:35, 17 March 2021 (UTC)

Disputed

I am creating a new section to better follow the guidelines in WP:DISPUTED.

showing reduced side effects, especially lacking respiratory depression, when administered in high doses in mice. Importantly, however, this brominated member of the series, while it is a potent μ-opioid agonist, lacks the safety margin seen for several other analogs

I did not see any animal studies for brorphine, although I have not yet looked into this extensively.

Moreover, its safety profile in any animal model has never been established.

Contradicting the previous statements! I won't yet remove these because I haven't looked for animal studies yet, but I will immediately after I do because of this contradiction.

and shows only limited functional bias, with an EC₅₀ of 4.8nM for GTPγS binding and 182nM for β-arrestin recruitment. Brorphine can instead be regarded as a typical opioid agonist, based upon its performance under various assay conditions, including robust arrestin recruitment.

Ironically, the figures on the bias of the compound oppose the claims made! There is the other study that reported a lack of bias for all compounds tested including brorphine, but this would seem to contradict all other papers on biased agonism including the original study discovering brorphine.

it is expected to be cardiotoxic because it is a potent hERG potassium ion channel inhibitor,

As I mentioned earlier, I believe this to be a totally false claim. I found many sources on this, with none being credible and all being after the original edit.

Given its potency, lack of functional bias, and hERG inhibition,^{[citation needed]} it can be expected to be a comparatively toxic opioid, and indeed multiple deaths from its abuse have been reported.

For now, I'm removing "lack of functional bias" and changing "toxic" to "dangerous", because toxic implies chronic toxicity rather than acute for many people. This is also somewhat contradictory with "Brorphine can instead be regarded as a typical opioid agonist".

This could be malicious attempt to give brorphine a bad name, although I am of course hesitant to assume bad faith. All of the claims I mentioned above were originally written by a single IP adress. Meodipt also made several edits, although these appear to be contradicting the dubious claims or simply writing them in a better way. The whole article needs citations as well. There aren't any more claims that I think are unlikely to be true, but citations are still necessary (for example, for the schedule 1 legality claim). Towelbin (talk) 02:07, 14 May 2021 (UTC)

I went ahead and removed the claims of hERG blocking and clarified information on the extent of functional selectivity. I’m going to rewrite information on functional selectivity of the compound to describe the conflict between the original paper and the newer one. I haven’t yet removed claims regarding animal testing or safety, but I likely will after I look for a citation on them. One of these will go however, as there is claimed to be a lack of animal studies on the compound while also claiming a lack of safety in mice!Towelbin (talk) 15:40, 14 May 2021 (UTC) updated 15:50, 14 May 2021 (UTC)

I have made all of the specified changes Towelbin (talk) 14:02, 18 May 2021 (UTC)

24.130.182.28 removed a sentence I wrote about the disputed nature of the lack of bias of brorphine. "I deleted the phrase 'This supposed lack of bias for all tested compounds may be questionable, as it would seem to conflict with all other research on biased agonism' because it's a fairly biased statement that has no place in this article, especially considering the fact that the biased agonism of brorphine itself has been thoroughly disproven" I'd like them to explain what they mean by this. The sentence was intended to show flaws in the study and question its accuracy, while still mentioning the questioned bias of brorphine. Please post more evidence debunking brorphine's bias. I don't think a single questionable paper with one citation on pubmed is thorough debunking. Towelbin (talk) 07:18, 4 June 2021 (UTC)

Related compounds

I no longer have access to Reaxys but I remember an analogue in which the 4-bromophenyl was replaced by a 2-thienyl moiety. The methyl side-chain had a huge impact on potency.

There were actually more potent homologues. If the 1H-benzimidazol-2-one moiety is substituted for a 1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one, affinity is increased by 2 orders of magnitude.

The post potent of the series had the 1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one & 2-thienyl moieties. If memory serves, the methyl side-chain is more active when (S) although it is my opinion that it's inclusion is not to increase affinity but rather to prevent hydrolysis of the compound.

Anyone with Reaxys can find it in 2 minutes simply by drawing the triazaspiro ring & searching through the (small number of) derivatives.

Of course such compounds are synthetically complex and the precursors costly. However, in a test set, the compound I mentioned had a higher affinity than 3R,4S,βS OHMeFentanyl (which had the third highest affinity - the 7-PET homologue of dihydroetorphine had the second highest (and that is said to be x40000 M).

The most active of the series are:

1)8-cyclodecyl-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one 2)8-(cis-4-isopropyl-cyclohexyl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one

Reference:

1)Bioorganic & Medicinal Chemistry Letters Volume 10, Issue 8, April 2000, Pages 831-834

'ORL1 receptor ligands: Structure–activity relationships of 8-cycloalkyl-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-ones'

2)Medicinal Chemistry, Volume 1, Number 6, 2005, pp. 601-610(10)

'8-(Heteroaryl)phenalkyl-1-Phenyl-1,3,8-triazaspiro[4.5]decan-4-ones as Opioid Receptor Modulators'

3)Bioorg Med Chem Lett. 1999 Aug 16;9(16):2343-8. doi: 10.1016/s0960-894x(99)00385-6.

'8-acenaphthen-1-yl-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one derivatives as orphanin FQ receptor agonists'

4)European Patent 1080091A1

5)European Patent 0856514

6)European Patent 0921125

7)European Patent P0921125B1

8)US Patent 6277991B1

9)US Patent 6277991B1

10) Australian Patent 1382901A

11)World Patent Application 2001036418A1 — Preceding unsigned comment added by 81.97.41.222 (talk) 01:12, 29 January 2022 (UTC)

Novel 1,3,8-triazaspiro[4.5]decanones with high affinity for opioid receptor subtypes

The compounds were further developed in:

A selective small molecule NOP (ORL-1 receptor) partial agonist for the treatment of anxiety.

Published 1 February 2015 Chemistry, Medicine Bioorganic & medicinal chemistry letters

Which includes the replacement of the p-Br phenyl moiety with a 2-thienyl moiety.

The sequence of patents show how the class was developed. The last 4 patents are of particular utility.