generation run 2026-05-12
63 min completedmodel pipeline-v5plan not recordedrun/af274ccd…Selection
Verification
- record
- seen / partial
- working
The model's own caveats
- sparse_evidence
- safety_data_unverified
- structural_inference
Reproduce
- inputs
- 17 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
16 searches — query, source, results, what was kept and why
| # | source | query | seen | kept | rationale |
|---|---|---|---|---|---|
| 1 | PubMed | methylnaphthidate | 2 | 2 | Both directly relevant; first provides metabolic data, second is a comprehensive review |
| 2 | PubChem | methylnaphthidate | 1 | 1 | Primary chemical identity record for methylnaphthidate |
| 3 | PubMed | naphthyl methylphenidate analog stimulant pharmacology | 3 | 3 | PMID 12954808 - key reinforcing efficacy data for HDMP-28 in NHPs; PMID 11461755 - original synthesis and pharmacology; PMID 36745029 - DAT/SERT pharmacology including naphthyl analog |
| 4 | OpenAlex | methylnaphthidate HDMP-28 stimulant | 2 | 1 | Only the metabolic study is relevant; MDMB-CHMICA is a synthetic cannabinoid unrelated to methylnaphthidate |
| 5 | WebSearch | methylnaphthidate HDMP-28 toxicity overdose death case report adverse event | 10 | 1 | Confirms absence of clinical toxicology case reports |
| 6 | ClinicalTrials.gov · absence | methylnaphthidate HDMP-28 | 0 | 0 | No trials found - confirms absence of clinical development |
| 7 | HandWiki | — | 1 | 3 | Aggregated reference data including binding affinities and legal status |
| 8 | NCATS Inxight Drugs | — | 1 | 2 | Official drug database entry confirming chemical identity and regulatory data |
| 9 | PubMed | methylphenidate analogues binding affinities dopamine serotonin transport sites synthesis | 5 | 1 | Davies 2004 provides an alternative synthesis and binding data specifically for naphthyl methylphenidate stereoisomers |
| 10 | PubMed | Luethi Liechti methylphenidate designer drug pharmacology monoamine transporter | 1 | 1 | Core pharmacology study for methylphenidate-based NPS; likely contains binding data |
| 11 | WebSearch | methylnaphthidate HDMP-28 legal status scheduled controlled substance UK US | 10 | 1 | Primary legal status data for major jurisdictions |
| 12 | WebSearch | HDMP-28 methylnaphthidate DAT NET SERT binding affinity IC50 Ki pharmacology | 10 | 1 | Key pharmacological binding data |
| 13 | edoc.unibas.ch | Luethi 2018 phenidate designer drugs pharmacology binding data | 1 | 1 | Critical clarification: this key pharmacology paper does NOT contain methylnaphthidate data |
| 14 | Research synthesis | All pharmacology, legal status, history, interactions data for HDMP-28 | 1 | 1 | Final synthesis of all gathered data for writing handoff document |
| 15 | WebSearch | HDMP-28 methylnaphthidate Australia New Zealand legal status | 10 | 1 | Confirmed multiple EU/UK jurisdictions but Australia/NZ data not found |
| 16 | PubMed | methylphenidate ethanol transesterification ethylphenidate pharmacokinetics interaction carboxylesterase | 3 | 3 | Documents the methylphenidate-alcohol transesterification interaction mechanism directly relevant to explaining the alcohol interaction flag for HDMP-28 |
52 claims by section — every cited sentence, checked against its source
safety12 · 11 ok
Compulsive redosing: The reinforcing efficacy equal to cocaine in non-human primate models predicts significant compulsive redosing risk in humans.supported
HDMP-28 showed reinforcing efficacy comparable to cocaine and methylphenidate in rhesus monkeys. pmid:12954808
Psychological dependence: Moderate to high, inferred directly from the non-human primate reinforcing efficacy data showing equivalence with cocainesupported
HDMP-28 showed reinforcing efficacy comparable to cocaine and methylphenidate in rhesus monkeys. pmid:12954808
No animal acute toxicity studies have been published, and no human fatalities attributed to the compound have been identified in the peer-reviewed literature or in the NPS adverse events review conducted by Mohr et al., which covered 1,319 cases involving over 60 novel psychoactive substances from 2017–2020.supported
Review of 1,319 NPS adverse event cases 2017-2020 covering 60+ NPS with confirmed adverse events. Methylnaphthidate not specifically listed among confirmed cases. bkac023
By pharmacological class, the acute toxicity risks of a potent DAT/NET/SERT reuptake inhibitor include cardiovascular crisis (hypertension, tachycardia, arrhythmia, vasoconstriction), CNS excitotoxicity (agitation, seizures), and hyperthermia — particularly with physical exertion or serotonergic co-exposuresupported
Dopaminergic stimulants inhibit DAT/NET and have high addiction liability. Serotonergic drugs risk serotonin syndrome, hyperthermia, seizures. smw.2015.14043
By pharmacological class, the acute toxicity risks of a potent DAT/NET/SERT reuptake inhibitor include cardiovascular crisis (hypertension, tachycardia, arrhythmia, vasoconstriction), CNS excitotoxicity (agitation, seizures), and hyperthermia — particularly with physical exertion or serotonergic co-exposuresupported
Stimulants primarily interact with monoamine transporters causing sympathomimetic toxicity. s00204-020-02693-7
Claim in safety — inconclusiveinconclusiveworking →
The combination of methylnaphthidate with serotonergic agents poses serotonin toxicity risk proportional to the degree of additive serotonin elevation. Tramadol — which combines serotonin/norepinephrine reuptake inhibition with serotonin release and opioid agonism — represents a particularly dangerous combination due to additive serotonergic stimulation compounded by seizure threshold reduction from both agents. MDMA, a potent serotonin releaser, combined with SERT blockade from methylnaphthidate, produces extreme serotonergic stimulation with risk of serotonin syndrome, hyperthermia, and cardiovascular crisissupported
Serotonergic drugs risk serotonin syndrome, hyperthermia, seizures. DAT/SERT ratio predicts psychotropic vs toxic effects. smw.2015.14043
The combination of methylnaphthidate with serotonergic agents poses serotonin toxicity risk proportional to the degree of additive serotonin elevation. Tramadol — which combines serotonin/norepinephrine reuptake inhibition with serotonin release and opioid agonism — represents a particularly dangerous combination due to additive serotonergic stimulation compounded by seizure threshold reduction from both agents. MDMA, a potent serotonin releaser, combined with SERT blockade from methylnaphthidate, produces extreme serotonergic stimulation with risk of serotonin syndrome, hyperthermia, and cardiovascular crisissupported
Comprehensive review of designer drug mechanism and adverse effects across NPS classes. Stimulants primarily interact with monoamine transporters causing sympathomimetic toxicity. s00204-020-02693-7
The combination of methylnaphthidate with serotonergic agents poses serotonin toxicity risk proportional to the degree of additive serotonin elevation. Tramadol — which combines serotonin/norepinephrine reuptake inhibition with serotonin release and opioid agonism — represents a particularly dangerous combination due to additive serotonergic stimulation compounded by seizure threshold reduction from both agents. MDMA, a potent serotonin releaser, combined with SERT blockade from methylnaphthidate, produces extreme serotonergic stimulation with risk of serotonin syndrome, hyperthermia, and cardiovascular crisissupported
Serotonergic drugs risk serotonin syndrome, hyperthermia, seizures. DAT/SERT ratio predicts psychotropic vs toxic effects. smw.2015.14043
Co-administration with ethanol may produce transesterification of the methyl ester to an ethyl ester (ethylnaphthidate) via carboxylesterase inhibition, by analogy with the well-characterized methylphenidate-ethanol interactionsupported
Ethanol co-administration elevates d-MPH concentrations 44-99% and forms l-ethylphenidate via transesterification. dmd.112.048595
Co-administration with ethanol may produce transesterification of the methyl ester to an ethyl ester (ethylnaphthidate) via carboxylesterase inhibition, by analogy with the well-characterized methylphenidate-ethanol interactionsupported
Reviews pharmaceutical science of ethylphenidate as transesterification product of methylphenidate+ethanol. CES1 enantioselectively transesterifies l-MPH with ethanol. jps.24202
Co-administration with ethanol may produce transesterification of the methyl ester to an ethyl ester (ethylnaphthidate) via carboxylesterase inhibition, by analogy with the well-characterized methylphenidate-ethanol interactionpartially supported
Ethanol coadministered with dl-MPH or d-MPH significantly increases Cmax of d-MPH 15-22%, elevates drug exposure and psychostimulant effects. jcp.0000000000000721
chemistry6 · 3 ok
The defining structural modification is replacement of the phenyl ring at the α-carbon with a 2-naphthyl (β-naphthalene) group, expanding the aromatic surface area and increasing lipophilicitysupported
Beta-naphthyl congener considerably more potent than methylphenidate at DAT. pmid:11461755
Claim in chemistry — inconclusiveinconclusiveworking →
Claim in chemistry — inconclusiveinconclusiveworking →
Claim in chemistry — inconclusiveinconclusiveworking →
The erythro-(2-naphthyl) diastereomers display a markedly different selectivity profile, with high binding affinity and selectivity for the serotonin transporter rather than the dopamine transportersupported
Erythro-(2-naphthyl) analogues display high binding affinity and selectivity for the serotonin transporter. pmid:15026075
The (αR,2S) pyrrolidine-ring isomer (HDMP-29) produces no reinforcing effects in non-human primate self-administration, demonstrating the critical role of ring size and stereochemistry in determining the behavioral pharmacology of this structural series.supported
HDMP-28 showed reinforcing efficacy comparable to cocaine and methylphenidate in rhesus monkeys; HDMP-29 did not. pmid:12954808
history5 · 5 ok
The β-naphthyl analog of methylphenidate was first synthesized by Deutsch, Ye, Shi, Liu, and Schweri in 2001 as part of a systematic exploration of methylphenidate structural modifications using the Blaise reactionsupported
Blaise reaction methodology for methylphenidate analogs. Beta-naphthyl congener considerably more potent than methylphenidate at DAT. pmid:11461755
The naphthyl congener proved "considerably more potent" than methylphenidate at the dopamine transporter, establishing the foundational pharmacological interest in the compound.supported
Beta-naphthyl congener considerably more potent than methylphenidate at DAT. pmid:11461755
Davies, Panmand, and Bhatt independently synthesized naphthyl methylphenidate analogs in 2004 using a rhodium(II)-catalyzed intermolecular C–H insertion approach, characterizing both dopamine and serotonin transporter binding for threo and erythro stereoisomerssupported
Rhodium(II)-catalyzed synthesis of methylphenidate analogues via intermolecular C-H insertion. Provides DAT/SERT binding affinity data for naphthyl isomers. pmid:15026075
The most consequential early study was Lile et al.'s 2003 investigation of reinforcing efficacy in rhesus monkeys (n = 9), which placed HDMP-28 on equal footing with cocaine and methylphenidate in progressive-ratio self-administration — the strongest available behavioral pharmacology evidence for the compound.supported
HDMP-28 showed reinforcing efficacy comparable to cocaine and methylphenidate in rhesus monkeys; HDMP-29 did not. pmid:12954808
The compound attracted forensic interest when it was identified as a potential doping agent in equestrian sports, prompting Ajeebsanu et al. to conduct a comprehensive metabolic investigation in equine liver microsomes and the fungal model Cunninghamella elegans in 2024supported
Comprehensive metabolic investigation of dopamine reuptake inhibitor HDMP-28 in equine liver microsomes and Cunninghamella elegans for doping control. dta.3642
pharmacology5 · 5 ok
The NCATS Inxight Drugs database describes it as "a potent dopamine reuptake inhibitor, with several times the potency of methylphenidate and a short duration of action", while Ajeebsanu et al. characterize HDMP-28 as surpassing methylphenidate "in both dopamine reuptake inhibition and half-life".supported
It surpasses methylphenidate in both dopamine reuptake inhibition and half-life. dta.3642
Jones et al. confirmed that the naphthyl methylphenidate counterpart acts at both human DAT and human SERT "rather uniquely relative to other members" of the phenidate series.supported
Naphthyl methylphenidate counterpart acts at hDAT and hSERT. Naphthyl compound has SERT activity unlike most phenidate analogs. acschemneuro.2c00666
NET inhibition is inferred from the compound's membership in the phenidate class, where NET activity is a consistent pharmacological featuresupported
In vitro pharmacological characterization of methylphenidate-based NPS; monoamine transporter inhibition potencies. j.neuropharm.2017.08.020
The compound's half-life is described as longer than that of methylphenidate (approximately 2–3 hours for the parent compound)supported
It surpasses methylphenidate in both dopamine reuptake inhibition and half-life. dta.3642
Ajeebsanu et al. identified 31 metabolites of HDMP-28 using equine liver microsomes and the fungal model Cunninghamella elegans: 22 Phase I metabolites (produced via hydroxylation of the naphthyl ring and piperidine ring, hydrogenation, and ester hydrolysis to a ritalinic acid analog) and 9 Phase II metabolites (glucuronic acid conjugates)supported
Study identifies 31 metabolites (22 phase I, 9 phase II) including hydroxylated, hydrogenated, hydrolyzed analogs and glucuronic acid conjugates in equine liver microsomes and Cunninghamella elegans. dta.3642
summary5 · 4 ok
Deutsch et al. first synthesized the compound in 2001 as part of a Blaise reaction–based series of methylphenidate analogs designed to probe structure-activity relationships relevant to cocaine abuse treatmentsupported
Blaise reaction methodology for methylphenidate analogs. Beta-naphthyl congener considerably more potent than methylphenidate at DAT; binding data from rat striatal tissue assays. pmid:11461755
The published evidence base is sparse: two synthesis papers, one non-human primate behavioral pharmacology study, and a 2024 equine metabolism investigation constitute the entirety of peer-reviewed substance-specific data.supported
HDMP-28, or methylnaphthidate, is a potent synthetic stimulant...Study identifies 31 metabolites (22 phase I, 9 phase II)...in equine liver microsomes and Cunninghamella elegans. dta.3642
Claim in summary — inconclusiveinconclusiveworking →
No LD₅₀ data exist in any species, and no human adverse event case reports have been publishedsupported
Review of 1,319 NPS adverse event cases 2017-2020 covering 60+ NPS with confirmed adverse events. Methylnaphthidate not specifically listed among confirmed cases. bkac023
In rhesus monkeys, HDMP-28 maintained reinforcing efficacy equal to cocaine and methylphenidate on progressive-ratio schedules, indicating substantial abuse liabilitysupported
HDMP-28 showed reinforcing efficacy comparable to cocaine and methylphenidate in rhesus monkeys; HDMP-29 did not. Potency correlated with DAT affinity. pmid:12954808
clinical-evidence4 · 4 ok
Deutsch et al. (2001): synthesis and DAT binding characterization of the racemic threo analog.supported
Blaise reaction methodology for methylphenidate analogs. Beta-naphthyl congener considerably more potent than methylphenidate at DAT; binding data from rat striatal tissue assays. pmid:11461755
Lile et al. (2003): reinforcing efficacy in rhesus monkeys (n = 9), progressive-ratio schedule, comparing HDMP-28 to cocaine, methylphenidate, and other phenidate analogs.supported
HDMP-28 showed reinforcing efficacy comparable to cocaine and methylphenidate in rhesus monkeys; HDMP-29 did not. Potency correlated with DAT affinity. pmid:12954808
Davies et al. (2004): alternative synthesis and DAT/SERT binding characterization of threo and erythro stereoisomers.supported
Rhodium(II)-catalyzed synthesis of methylphenidate analogues via intermolecular C-H insertion. Provides DAT/SERT binding affinity data for naphthyl isomers. pmid:15026075
A single forensic/analytical study — Ajeebsanu et al. (2024) — characterized the metabolic profile in equine liver microsomes for doping control purposes but did not report human pharmacological endpoints.supported
Comprehensive metabolic investigation of dopamine reuptake inhibitor HDMP-28 in equine liver microsomes and Cunninghamella elegans for doping control. dta.3642
comparative-pharmacology4 · 3 ok
In rhesus monkey progressive-ratio self-administration, the rank ordering of reinforcing efficacy was: cocaine = methylphenidate = HDMP-28 ≥ HD-60 ≥ PTT ≥ HD-23 > HDMP-29supported
HDMP-28 showed reinforcing efficacy comparable to cocaine and methylphenidate in rhesus monkeys; HDMP-29 did not. pmid:12954808
Potency to maintain peak breaking points correlated significantly with DAT affinity across the panel, suggesting that DAT occupancy dynamics — rather than simple pharmacokinetics — are the primary determinants of reinforcing efficacy in this paradigm.supported
Potency correlated with DAT affinity. pmid:12954808
Claim in comparative-pharmacology — inconclusiveinconclusiveworking →
Luethi separately demonstrated that in vitro monoamine transporter interaction profiles can predict reported human active doses for novel psychoactive stimulants, a framework applicable to methylnaphthidate dose estimation pending direct transporter characterization of the pure enantiomer.supported
In vitro pharmacological profiles of NPS predict psychoactive doses; transporter potency ratios correlate with active dose ranges for stimulants. pyy047
neuroscience4 · 2 ok
Claim in neuroscience — inconclusiveinconclusiveworking →
This dopaminergic potentiation underlies the reinforcing efficacy demonstrated in non-human primates, where HDMP-28 maintained self-administration behavior equivalent to cocaine.supported
HDMP-28 showed reinforcing efficacy comparable to cocaine and methylphenidate in rhesus monkeys. Potency correlated with DAT affinity. pmid:12954808
Lile et al. found that peak breaking points in progressive-ratio schedules correlated with DAT affinity rather than pharmacokinetic parameters, suggesting rapid DAT occupancy as the mechanistic driver of abuse potentialsupported
Potency correlated with DAT affinity. pmid:12954808
Claim in neuroscience — inconclusiveinconclusiveworking →
pharmacokinetic-detail4 · 4 ok
The sole published metabolic study employed equine liver microsomes and the fungal model Cunninghamella elegans as surrogates for mammalian metabolismsupported
Study identifies 31 metabolites...in equine liver microsomes and Cunninghamella elegans. dta.3642
By structural analogy with methylphenidate, co-administration with ethanol may produce transesterification via carboxylesterase inhibition, potentially generating ethylnaphthidate in vivosupported
Ethanol co-administration elevates d-MPH concentrations 44-99% and forms l-ethylphenidate via transesterification. dmd.112.048595
By structural analogy with methylphenidate, co-administration with ethanol may produce transesterification via carboxylesterase inhibition, potentially generating ethylnaphthidate in vivosupported
Reviews pharmaceutical science of ethylphenidate as transesterification product of methylphenidate+ethanol. CES1 enantioselectively transesterifies l-MPH with ethanol. jps.24202
Patrick et al. characterized this transesterification mechanism for methylphenidate, demonstrating that ethanol co-exposure produces ethylphenidate with altered pharmacokinetic propertiespartially supported
Ethanol coadministered with dl-MPH or d-MPH significantly increases Cmax of d-MPH 15-22%, elevates drug exposure and psychostimulant effects. jcp.0000000000000721
receptor-pharmacology3 · 3 ok
The most direct binding data derive from Deutsch et al.'s characterization of the racemic threo naphthyl methylphenidate analog, aggregated via HandWiki:supported
Beta-naphthyl congener considerably more potent than methylphenidate at DAT; binding data from rat striatal tissue assays. pmid:11461755
NET inhibition is inferred from the phenidate structural class, where Luethi et al. demonstrated that all characterized methylphenidate-based substances inhibit NET and DAT 4- to >1000-fold more potently than SERT — though that study characterized ethylnaphthidate rather than methylnaphthidate.supported
In vitro pharmacological characterization of methylphenidate-based NPS; monoamine transporter inhibition potencies. j.neuropharm.2017.08.020
Davies et al. reported "high binding affinity and selectivity for the serotonin transporter" in erythro-(2-naphthyl) analogs, in contrast to the DAT-preferring threo isomer HDMP-28supported
Erythro-(2-naphthyl) analogues display high binding affinity and selectivity for the serotonin transporter. pmid:15026075