generation run 2026-05-08
62 min completedmodel pipeline-v5plan not recordedrun/ca8e0743…Selection
Verification
- record
- seen / partial
- working
The model's own caveats
- sparse_evidence
- safety_data_unverified
Reproduce
- inputs
- 28 source keys (listed under Sources)
- plan
- not recorded — template version, prompt hash and git SHA are written from 2026-09 onward
- model
- pipeline-v5
- streams
- none — agent transcripts are persisted from 2026-09 onward
20 searches — query, source, results, what was kept and why
| # | source | query | seen | kept | rationale |
|---|---|---|---|---|---|
| 1 | OpenAlex | brorphine synthetic opioid | 10 | 3 | — |
| 2 | PubMed | PMID 34233349 - Vandeputte et al. 2021 Rise and Fall brorphine | 1 | 1 | — |
| 3 | PubChem | brorphine | 1 | 1 | — |
| 4 | PubMed | PMID 34509061 - Grafinger et al. 2021 brorphine metabolism | 1 | 1 | — |
| 5 | PubMed | brorphine opioid | 15 | 11 | — |
| 6 | ClinicalTrials.gov · absence | brorphine | 0 | 0 | — |
| 7 | PubMed | PMID 30199635 - Kennedy 2018 piperidine benzimidazolone MOR agonists source paper | 1 | 1 | — |
| 8 | PubMed | PMID 32734307 - Vandeputte 2020 in vitro panel non-fentanyl opioid NPS | 1 | 1 | — |
| 9 | WebSearch | brorphine potency morphine EC50 Ki nM radioligand binding MOR | 8 | 1 | — |
| 10 | UK Government / ACMD (WebSearch) | brorphine UK Misuse of Drugs Act Class A scheduling date 2022 2023 ACMD recommendation | 5 | 2 | — |
| 11 | WebSearch | brorphine original patent synthesis history Janssen Kennedy 2018 | 8 | 2 | — |
| 12 | PubMed | PMID 32744605 - Verougstraete et al. 2021 First Report on Brorphine | 1 | 1 | — |
| 13 | Federal Register (WebSearch/WebFetch) | brorphine DEA Schedule I emergency scheduling 2021 federal register | 5 | 2 | — |
| 14 | UNODC EWA (WebFetch) | UNODC 2020 brorphine emerging synthetic opioid | 1 | 1 | — |
| 15 | UNODC EWA (WebFetch) | UNODC 2025 emerging analogues of brorphine | 1 | 1 | — |
| 16 | WebSearch | brorphine stereochemistry SMILES CAS physical properties | 8 | 0 | — |
| 17 | WebSearch | brorphine Canada Australia New Zealand scheduling controlled substance status | 8 | 2 | — |
| 18 | PubMed | PMID 33201526 - Krotulski 2021 brorphine forensic casework | 1 | 1 | — |
| 19 | Multiple sources | Potency comparison: brorphine vs morphine vs fentanyl | 5 | 3 | — |
| 20 | PubMed | PMID 33522844 - Vohra 2021 death associated with brorphine | 1 | 1 | — |
74 claims by section — every cited sentence, checked against its source
safety17 · 15 ok
Testing with S9 metabolic activation also showed no genotoxicity, suggesting metabolites do not confer additional genotoxic risksupported
Brorphine and orphine showed NO significant micronuclei increase; not genotoxic even with S9 metabolic activation. ijms26115084
Claim in safety — inconclusiveinconclusiveworking →
For some compounds in the piperidine benzimidazolone class, naloxone pretreatment at 6 mg/kg IP did not fully reverse respiratory depressionsupported
naloxone pretreatment could not fully reverse for some compounds. j.neuropharm.2024.110113
Amaducci et al. reported that patients testing positive for novel potent opioids (NPOs, including brorphine) received a mean of 1.33 ± 1.50 in-hospital naloxone boluses compared to 0.36 ± 0.92 for fentanyl-only patients (P = 0.02, Cohen d = 0.78).supported
NPO group received significantly higher naloxone boluses than fentanyl group (1.33 vs 0.36, P=0.02, Cohen d=0.78). jamanetworkopen.2023.31264
Over 100 deaths in 2020supported
Describes brorphine as full MOR agonist involved in >100 deaths in 2020. jox12040025
91 brorphine-positive postmortem blood samples in a single US forensic laboratory series (January 2020–December 2021), making it the third most prevalent NSO after isotonitazene (n = 144) and metonitazene (n = 122)supported
384 NSO-positive postmortem blood samples Jan 2020-Dec 2021. Brorphine was 3rd most prevalent (n=91). paf.0000000000000787
Claim in safety — inconclusiveinconclusiveworking →
Of 20 forensic cases analyzed by Krotulski et al., 100% showed fentanyl co-use and 80% showed flualprazolam co-usesupported
100% co-found with fentanyl, 80% with flualprazolam. 1556-4029.14623
As a high-efficacy MOR full agonist with Emax exceeding hydromorphone by >2.6-fold, brorphine carries presumptive high risk for:supported
Brorphine had highest Emax values exceeding hydromorphone ≥1.3-fold (β-arr2) and >2.6-fold (mini-Gi). s00204-020-02855-7
The single published clinical case — a patient presenting for detoxification — suggests human dependence develops, but no characterization of psychological distress, craving intensity, or psychiatric comorbidity was reported.supported
Powder obtained from patient seeking detoxification. bkaa094
One clinical case documents a patient seeking detoxification, confirming human dependence potentialsupported
Powder obtained from patient seeking detoxification. bkaa094
Fentanyl: 100% co-detection rate across 20 forensic cases. Dual MOR agonism amplifies respiratory depression through additive receptor activation.supported
100% co-found with fentanyl. 1556-4029.14623
Benzodiazepines: 80% of forensic cases showed flualprazolam co-use. GABAergic depression combined with opioid respiratory suppression dramatically increases overdose mortality. This polydrug pattern is documented in confirmed fatalities.supported
80% with flualprazolam. Majority from Midwestern US states. 1556-4029.14623
Full reversal may require higher or repeated dosessupported
naloxone pretreatment could not fully reverse for some compounds. j.neuropharm.2024.110113
Full reversal may require higher or repeated dosessupported
NPO group received significantly higher naloxone boluses than fentanyl group (1.33 vs 0.36, P=0.02, Cohen d=0.78). jamanetworkopen.2023.31264
Respiratory compromise: Any pre-existing respiratory insufficiency (COPD, sleep apnea, acute asthma) is an absolute contraindication given brorphine's pronounced respiratory depressant activity, compounded by the documented difficulty of naloxone reversal.supported
brorphine respiratory depression at 15 mg/kg IP; naloxone pretreatment could not fully reverse for some compounds. j.neuropharm.2024.110113
Concurrent CNS depressant use: Co-administration with benzodiazepines, other opioids, barbiturates, or alcohol represents an absolute contraindication supported by forensic mortality data.supported
100% co-found with fentanyl, 80% with flualprazolam. 1556-4029.14623
pharmacology12 · 12 ok
MOR activation by brorphine produces canonical Gαi/o signaling, leading to inhibition of adenylyl cyclase and reduction of intracellular cAMP, alongside recruitment of β-arrestin2supported
Brorphine had highest Emax values exceeding hydromorphone ≥1.3-fold (β-arr2) and >2.6-fold (mini-Gi). No significant biased agonism. s00204-020-02855-7
MOR activation by brorphine produces canonical Gαi/o signaling, leading to inhibition of adenylyl cyclase and reduction of intracellular cAMP, alongside recruitment of β-arrestin2supported
All bind MOR with nM affinity. No significant biased agonism. j.neuropharm.2024.110113
No significant biased agonism toward either the G-protein or β-arrestin pathway has been demonstrated relative to the comparator hydromorphonesupported
No significant biased agonism. First systematic in vitro characterization of non-fentanyl NPS panel including brorphine. s00204-020-02855-7
No significant biased agonism toward either the G-protein or β-arrestin pathway has been demonstrated relative to the comparator hydromorphonesupported
No significant biased agonism. j.neuropharm.2024.110113
This absence of bias is notable given that the compound was originally synthesized within a series explicitly optimized for G-protein-biased MOR agonism.supported
Synthesis and optimization of piperidine benzimidazolone MOR agonists with high G protein signaling bias. acs.jmedchem.8b01136
Brorphine also acts as a weak partial agonist at the kappa-opioid receptor (KOR), as confirmed in [³⁵S]-GTPγS functional assayssupported
potent MOR agonist, weak partial KOR agonist. j.forsciint.2021.110989
Grafinger et al. identified 14 distinct metabolites in human urine and 4 in blood from forensic cases, alongside 6 phase I metabolites generated in vitro using pooled human liver microsomessupported
14 in vivo metabolites in urine, 4 in blood; main in vivo metabolite by N-oxidation. j.forsciint.2021.110989
The primary in vivo metabolite was formed by N-oxidation, while the primary in vitro metabolite resulted from hydroxylationpartially supported
main in vivo metabolite by N-oxidation. j.forsciint.2021.110989
N-dealkylation and hydroxylation were confirmed as metabolic pathways in authenticated forensic cases by Krotulski et al.supported
Metabolism: N-dealkylation and hydroxylation. 1556-4029.14623
Verougstraete et al. identified a hydroxy-metabolite in patient serum from the first clinical case.supported
Serum sample found brorphine plus hydroxy-metabolite. bkaa094
Across 20 forensic cases, mean blood concentration was 2.5 ± 3.1 ng/mL (median 1.1 ng/mL; range 0.1–10 ng/mL), with mean urine concentration of 4.6 ± 7.6 ng/mL (median 1.6 ng/mL; range 0.2–23 ng/mL)supported
Avg blood 2.5±3.1 ng/mL (median 1.1, range 0.1-10 ng/mL); avg urine 4.6±7.6 ng/mL (median 1.6, range 0.2-23). 1556-4029.14623
Kennedy et al. reported that piperidine benzimidazolone compounds in this series possess long half-lives and high brain penetration as pharmacological properties, though no specific human half-life values were publishedsupported
Compounds have long half-lives and high brain penetration. acs.jmedchem.8b01136
summary10 · 8 ok
Claim in summary — inconclusiveinconclusiveworking →
Duration data have not been formally characterized, though the compound class is reported to exhibit long half-lives and high brain penetration.supported
Compounds have long half-lives and high brain penetration. acs.jmedchem.8b01136
Brorphine's structure was derived from a 2018 medicinal chemistry publication investigating G-protein-biased MOR agonists as potentially safer analgesicssupported
Synthesis and optimization of piperidine benzimidazolone MOR agonists with high G protein signaling bias. The source paper from which brorphine's structure was derived for illicit synthesis. acs.jmedchem.8b01136
The compound was appropriated from this academic work and appeared on illicit markets by mid-2019, rapidly becoming the dominant non-fentanyl NSO in the United States after isotonitazene was emergency-scheduled in June 2020supported
Emerged mid-2019, dominated NPS market 2020, contributed to hundreds of deaths and adverse events. Opioids pirated from patent literature. bkab082
Claim in summary — inconclusiveinconclusiveworking →
Its maximal efficacy exceeds that of hydromorphone by more than 2.6-fold in the mini-Gαi recruitment assay, indicating a high-efficacy full agonist profilesupported
Brorphine had highest Emax values exceeding hydromorphone ≥1.3-fold (β-arr2) and >2.6-fold (mini-Gi). s00204-020-02855-7
No significant G-protein/β-arrestin bias has been demonstrated relative to hydromorphone.supported
No significant biased agonism. j.neuropharm.2024.110113
Brorphine poses critical overdose risk through pronounced respiratory depression confirmed in animal models, with the additional hazard that naloxone pretreatment at high doses (6 mg/kg IP) could not fully reverse respiratory depression for some compounds in this classsupported
brorphine respiratory depression at 15 mg/kg IP; naloxone pretreatment could not fully reverse for some compounds. j.neuropharm.2024.110113
Emergency department data confirm that patients exposed to brorphine-class opioids required significantly more naloxone boluses than fentanyl-only patients (mean 1.33 vs 0.36; P = 0.02)supported
NPO group (brorphine, isotonitazene, metonitazene, N-piperidinyl etonitazene) received significantly higher naloxone boluses than fentanyl group (1.33 vs 0.36, P=0.02, Cohen d=0.78). jamanetworkopen.2023.31264
No controlled toxicity, pharmacokinetic, tolerance, or dependence studies exist for brorphine — all human exposure data derive from forensic casework, where 100% of cases showed fentanyl co-use and 80% showed concurrent flualprazolamsupported
100% co-found with fentanyl, 80% with flualprazolam. 1556-4029.14623
history7 · 6 ok
The specific compound brorphine appeared in the published literature in 2018, when Kennedy et al. described it within a series of piperidine benzimidazolone MOR agonists optimized for high G-protein signaling biassupported
Synthesis and optimization of piperidine benzimidazolone MOR agonists with high G protein signaling bias. acs.jmedchem.8b01136
The stated research goal was to develop analgesics with reduced respiratory depression liability through biased agonism — an objective that subsequent pharmacological characterization of brorphine would fail to support, as no significant bias was ultimately demonstrated.supported
No significant biased agonism. First systematic in vitro characterization of non-fentanyl NPS panel including brorphine. s00204-020-02855-7
Brorphine was appropriated directly from the Kennedy et al. 2018 publication and manufactured for illicit distributionsupported
Opioids pirated from patent literature. bkab082
Claim in history — inconclusiveinconclusiveworking →
When isotonitazene was emergency-scheduled by the DEA in June 2020, brorphine became the dominant non-fentanyl NSO in the United States, effectively replacing isotonitazene in illicit supply chainssupported
Emerged after isotonitazene scheduling mid-2020. 1556-4029.14623
During this peak period, brorphine was involved in over 100 deaths in 2020 alonesupported
Describes brorphine as full MOR agonist involved in >100 deaths in 2020. jox12040025
Online discussions of brorphine on recreational drug forums preceded laboratory toxicology detections, an observation confirmed through systematic surveillance of Reddit by Barenholtz et al.supported
Reddit discussion monitoring as predictor of NPS exposures; brorphine mentioned in online discussions preceding toxicology detections. j.drugpo.2021.103393
comparative-pharmacology6 · 2 ok
Claim in comparative-pharmacology — inconclusiveinconclusiveworking →
Claim in comparative-pharmacology — inconclusiveinconclusiveworking →
Claim in comparative-pharmacology — inconclusiveinconclusiveworking →
This elevated Emax correlates with the pronounced respiratory depression observed in animal models.supported
Chlorphine, brorphine, iodorphine most active MOR agonists. brorphine respiratory depression at 15 mg/kg IP. j.neuropharm.2024.110113
Claim in comparative-pharmacology — inconclusiveinconclusiveworking →
Brorphine and chlorphine emerge as the most pharmacologically active members of the benzimidazolone series across MOR binding, G-protein signaling, β-arrestin2 recruitment, and in vivo antinociceptionpartially supported
Chlorphine, brorphine, iodorphine most active MOR agonists. In vivo (CD-1 mice): brorphine+chlorphine highest antinociception. j.neuropharm.2024.110113
neuroscience5 · 4 ok
Claim in neuroscience — inconclusiveinconclusiveworking →
The finding that naloxone pretreatment (6 mg/kg IP) failed to fully reverse respiratory depression for some compounds in this class raises the possibility of additional non-MOR mechanisms contributing to respiratory suppression, though this remains speculative.supported
naloxone pretreatment could not fully reverse for some compounds. j.neuropharm.2024.110113
Given brorphine's Emax exceeding hydromorphone by >2.6-fold, the magnitude of dopaminergic disinhibition is expected to be substantial, though this has not been measured directly.supported
Brorphine had highest Emax values exceeding hydromorphone ≥1.3-fold (β-arr2) and >2.6-fold (mini-Gi). s00204-020-02855-7
The absence of G-protein/β-arrestin bias in brorphine suggests tolerance development patterns would resemble those of morphine and hydromorphone rather than biased agonists.supported
No significant biased agonism. s00204-020-02855-7
Brain penetration kinetics: Kennedy et al. describe high brain penetration for the class, but no CNS partitioning data (brain:plasma ratios) have been published for brorphine specifically.supported
Compounds have long half-lives and high brain penetration. acs.jmedchem.8b01136
pharmacokinetic-detail4 · 3 ok
Claim in pharmacokinetic-detail — inconclusiveinconclusiveworking →
The most comprehensive metabolic characterization comes from Grafinger et al., who identified 14 metabolites in human urine and 4 in blood from forensic cases, alongside 6 phase I metabolites generated using pooled human liver microsomessupported
14 in vivo metabolites in urine, 4 in blood; main in vivo metabolite by N-oxidation. j.forsciint.2021.110989
Clinical detection: Hydroxy-metabolite identified in patient serumsupported
Serum sample found brorphine plus hydroxy-metabolite. bkaa094
Oral fluid: FPSE-LC-MS/MS with LOD of 0.015 ng/mLsupported
First FPSE method for brorphine in oral fluid. LOD 0.015 ng/mL. jox12040025
receptor-pharmacology4 · 3 ok
Claim in receptor-pharmacology — inconclusiveinconclusiveworking →
Despite originating from a medicinal chemistry program targeting G-protein-biased MOR agonism, brorphine does not demonstrate significant functional selectivitysupported
Synthesis and optimization of piperidine benzimidazolone MOR agonists with high G protein signaling bias. acs.jmedchem.8b01136
In both β-arrestin2 and mini-Gαi recruitment assays in HEK 293T cells, brorphine's signaling profile parallels that of hydromorphonesupported
No significant biased agonism. j.neuropharm.2024.110113
SAR analysis of the piperidine benzimidazolone series establishes that the N-substituent — specifically the 1-(4-halophenyl)ethyl group — is the primary determinant of MOR binding potency, rather than modifications to the benzimidazolone coresupported
Side-chain functionalization primarily determines binding potency for non-fentanyl scaffolds. biomolther.2025.255
chemistry3 · 1 ok
Claim in chemistry — inconclusiveinconclusiveworking →
Claim in chemistry — inconclusiveinconclusiveworking →
Structure-activity relationship (SAR) analysis of the piperidine benzimidazolone series establishes the N-substituent — in brorphine's case, the 1-(4-bromophenyl)ethyl group — as the key determinant of binding potency, rather than the core benzimidazolone scaffoldsupported
Side-chain functionalization primarily determines binding potency for non-fentanyl scaffolds. biomolther.2025.255
clinical-evidence3 · 3 ok
Amaducci et al. conducted a retrospective cohort study of emergency department patients presenting with opioid overdose, comparing those testing positive for novel potent opioids (NPOs, including brorphine) against fentanyl-only patientssupported
Cohort study; NPO group (brorphine, isotonitazene, metonitazene, N-piperidinyl etonitazene) received significantly higher naloxone boluses than fentanyl group. jamanetworkopen.2023.31264
Verougstraete et al. reported the earliest published clinical case: a patient presenting for detoxification from brorphinesupported
First report on identification and full chemical characterization of brorphine. Powder obtained from patient seeking detoxification. bkaa094
Krotulski et al. documented 20 forensic cases with quantified blood and urine brorphine concentrationssupported
20 authentic forensic cases confirmed. Avg blood 2.5±3.1 ng/mL... avg urine 4.6±7.6 ng/mL. 1556-4029.14623
effects-overview2 · 2 ok
Its pharmacological profile — high-efficacy MOR full agonism with Emax exceeding hydromorphone by >2.6-fold, negligible biased agonism, and substantial MOR selectivity over DOR and KOR — predicts an experience dominated by opioid-typical euphoria, analgesia, sedation, and anxiolysissupported
Brorphine had highest Emax values exceeding hydromorphone ≥1.3-fold (β-arr2) and >2.6-fold (mini-Gi). No significant biased agonism. s00204-020-02855-7
The universal polydrug context of documented human exposures (100% fentanyl co-use, 80% flualprazolam) means that no observation of brorphine's isolated subjective character exists in the published literature.supported
100% co-found with fentanyl, 80% with flualprazolam. 1556-4029.14623
botanical-overview1 · 1 ok
The piperidine benzimidazolone scaffold was designed in pharmaceutical laboratories, and brorphine itself was first described as part of a synthetic medicinal chemistry series.supported
Synthesis and optimization of piperidine benzimidazolone MOR agonists with high G protein signaling bias. acs.jmedchem.8b01136