Talk:Sunobinop

Sunobinop
Clinical data
Other names	IMB-115, V117957
Drug class	Nociceptin receptor agonist
Identifiers
	IUPAC name 4-[(1R,5S)-9-[(1S,5S)-3-bicyclo[3.3.1]nonanyl]-9-azabicyclo[3.3.1]nonan-3-yl]-3-oxoquinoxaline-2-carboxylic acid;
CAS Number	1126793-40-5;
PubChem CID	155801560;
ChemSpider	34950269;
UNII	I1X86U5474;
ChEMBL	ChEMBL4650344;
Chemical and physical data
Formula	C26H33N3O3
Molar mass	435.568 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES O=C(O)C1=NC=2C=CC=CC2N(C1=O)C3CC4N(C(CCC4)C3)C5CC6CCCC(C5)C6;
	InChI InChI=1S/C26H33N3O3/c30-25-24(26(31)32)27-22-9-1-2-10-23(22)29(25)21-14-18-7-4-8-19(15-21)28(18)20-12-16-5-3-6-17(11-16)13-20/h1-2,9-10,16-21H,3-8,11-15H2,(H,31,32)/t16-,17-,18-,19+,21?/m0/s1; Key:COTYYZPYDJKKIS-MCXOOUIESA-N;

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ImbriumValentine (talk · contribs) has been paid by Imbrium Therapeutics. Disclosure

Sunobinop article improvements

This edit request by an editor with a conflict of interest has now been answered.

Hello! My name is Valentine, I'm an employee of Imbrium, the company developing sunobinop. I joined Wikipedia to put forth a more accurate, and in doing so, comprehensive description of sunobinop. I understand that because of my financial conflict I cannot make the changes to the article directly. I've prepared the infobox and text below that I think makes the article more accurate and up to date. Would someone here be willing to review and implement if it looks good? As I'm here, I welcome others to make any changes needed to meet Wikipedia's standards.

Extended content

Sunobinop (developmental code names V117957; IMB-115) is an investigational drug under study. It is a novel, high affinity, high-potency, small molecule agonist of the nociceptin/orphanin-FQ peptide (NOP) receptor. Sunobinop has nanomolar affinity (K_i) and efficacy (EC₅₀) at human recombinant NOP receptors. It has low binding affinity for mu, kappa and delta opioid receptors (K_i >1500 nM). It also has a high degree of functional selectivity for the NOP receptor as its EC50 against mu, delta and kappa receptors is between 500- and 5000-fold greater than for the NOP receptor.^[1] Sunobinop was generally well tolerated in 3 studies involving 70 healthy subjects at doses that ranged from 0.6 to 30 mg. The most prominent adverse event was dose-dependent sedation/somnolence, which was more common at doses greater than 10 mg. In these studies, the majority of absorbed sunobinop was excreted unchanged via rapid renal elimination.^[2] As of Feb 2024, it is under clinical investigation for the treatment of insomnia/alcohol use disorder, interstitial cystitis, and overactive bladder.^[3] The safety and effectiveness of sunobinop has not been evaluated by the FDA. There is no guarantee that sunobinop will successfully complete development or gain FDA approval.^[3]

References

^ Whiteside GT, Kyle DJ, Kapil RP, Cipriano A, He E, Zhou M, Shet MS, Hummel M, Knappenberger T, Fukumura K, Matsuo Y, Uehira M, Hiroyama S, Takai N, Willsie SK, Harris SC (January 2024). "The nociceptin/orphanin FQ receptor partial agonist sunobinop promotes non-REM sleep in rodents and patients with insomnia". The Journal of Clinical Investigation. 134 (1). doi:10.1172/JCI171172. PMC 10760950. PMID 37883189.
^ Cipriano A, Kapil RP, Zhou M, Shet MS, Whiteside GT, Willsie SK, Harris SC (March 13, 2024). "Safety, Tolerability, and Pharmacokinetics of Single- and Multiple-Ascending Doses of Sunobinop in Healthy Participants". Clinical Pharmacology in Drug Development. doi:10.1002/cpdd.1394. Retrieved May 1, 2024.
^ ^a ^b "Pipeline". Imbrium Therapeutics. Retrieved May 1, 2024.

Thank you for taking a look, and drop me a line if you have any questions. ImbriumValentine (talk) 19:13, 3 May 2024 (UTC)[reply]

Thanks for this requested edit:

You say "potent", and the current text says "partial agonist" - are you happy that both are correct (they can be, if the intrinsic efficacy is close to one, noting that the affinity is high).
It's often helpful to use sections to help readers identify relevant text (it helps with readability on mobile devices too
Your suggested text has no Wikilinks, which makes it inappropriate to substitute directly
You write "low binding affinity for mu, kappa and delta opioid receptors (K_i >1500 nM)", but 1.5microM isn't 'low' in the content of small-molecule affinity; just keeping the following sentence on relative affinity seems sufficient
You write "EC50"; do you mean the (inhibitory) EC50, or did you mean IC50?

So, I've made some edits reflecting your request and adding most of you content. I've marked the template as 'accepted' (done), even though I haven't done this precisely as you request. Please review and ping me if you'd like anything I've done corrected. Klbrain (talk) 09:00, 7 May 2024 (UTC)[reply]

@Klbrain: Thanks for promptly acting on my request and your constructive edits to the post! I wish to make one further clarification. As described by Whiteside et al (Ref 4 - Data found in supplementary materials), sunobinop is only an antagonist at mu and kappa receptors (with much weaker binding affinity, ~1.6uM and ~2uM respectively, as compared to Ki at NOP, 3.3nM) and a weak (low affinity, Ki ~5uM) partial (16% Emax) agonist at delta receptors. The AdisInsight reference that is cited is incorrect in referring to sunobinop as a pan-opioid antagonist. As per data above from Ref 4 the predominant action is at NOP with a wide margin of selectivity. Given this would the following additional minor edits be acceptable?

Change "...is a high affinity small molecule nociceptin receptor partial agonist and weak opioid antagonist." to "...is a high affinity small molecule nociceptin receptor partial agonist." and change the citation to Whiteside et al.
Following "...receptors is between 500- and 5000-fold greater than for the NOP receptor." add "Sunobinop does not activate human mu and kappa opioid receptors and is a low affinity weak partial agonist at human delta opioid receptors." per Whiteside et al.
Move Harris et al (Ref 3) to the end of the previous sentence, it verifies the "insomnia" claim.

Thanks again! Let me know if you have any questions. ImbriumValentine (talk) 17:58, 8 May 2024 (UTC)[reply]

First point: agree, in particular that the mention of the opioid receptor effect doesn't need to be in the lede, and is elsewhere in the article.

Second point: 'Does not activate' is true but incomplete - it does bind to the mu and kappa, and source does describe them as an antagonist at these receptors; agree with the comments re: human delta receptors

Third point: Agree.

I've made edits consistent with the above. Klbrain (talk) 18:52, 8 May 2024 (UTC)[reply]

@Klbrain: Looks good, thanks again! ImbriumValentine (talk) 18:12, 9 May 2024 (UTC)[reply]

[pmid37883189-1] Whiteside GT, Kyle DJ, Kapil RP, Cipriano A, He E, Zhou M, Shet MS, Hummel M, Knappenberger T, Fukumura K, Matsuo Y, Uehira M, Hiroyama S, Takai N, Willsie SK, Harris SC (January 2024). "The nociceptin/orphanin FQ receptor partial agonist sunobinop promotes non-REM sleep in rodents and patients with insomnia". The Journal of Clinical Investigation. 134 (1). doi:10.1172/JCI171172. PMC 10760950. PMID 37883189.

[ACCP_2024-2] Cipriano A, Kapil RP, Zhou M, Shet MS, Whiteside GT, Willsie SK, Harris SC (March 13, 2024). "Safety, Tolerability, and Pharmacokinetics of Single- and Multiple-Ascending Doses of Sunobinop in Healthy Participants". Clinical Pharmacology in Drug Development. doi:10.1002/cpdd.1394. Retrieved May 1, 2024.

[ImbriumPipeline-3] "Pipeline". Imbrium Therapeutics. Retrieved May 1, 2024.

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