DOPR

# Research Output: DOPR

## Chemical Identity

**Verified via PubChem (CID 542051) [Ref 21] and NCATS Inxight Drugs [Ref 21]:**

- **Common name:** DOPR (also rendered DOPr)
- **Systematic/chemical name:** 2,5-Dimethoxy-4-(n-)propylamphetamine; also 1-(2,5-dimethoxy-4-propylphenyl)propan-2-amine
- **IUPAC name:** 1-(2,5-dimethoxy-4-propylphenyl)propan-2-amine
- **Molecular formula:** C₁₄H₂₃NO₂
- **Molecular weight:** 237.34 g/mol
- **Canonical SMILES:** CCCC1=CC(OC)=C(CC(C)N)C=C1OC [Ref 21]
- **InChIKey:** UEEAUFJYLUJWQJ-UHFFFAOYSA-N
- **CAS number (free base):** 63779-88-4 [Ref 21]
- **CAS number (HCl salt):** 53581-55-8 [Ref 20]
- **PubChem CID:** 542051
- **FDA UNII:** L3P287BI9W
- **Melting point (HCl salt):** 182.5–183°C [Ref 7]

**Structural context:** DOPR is a member of the DOx (2,5-dimethoxy-4-substituted amphetamine) chemical class. It is the 4-propyl homologue of DOM (4-methyl) and DOET (4-ethyl), differing from DOM by replacement of the methyl group at C-4 with a propyl chain. The alpha-methyl group on the aminopropyl side chain creates one chiral center. Commercially available DOPR is the racemic mixture, with 0 defined stereocenters declared in the NCATS registry [Ref 21].

**Brief discrepancy note:** The Psychedex database entry for DOPR contains no SMILES, molecular formula, molecular weight, or InChIKey. All have been confirmed and populated above from PubChem and NCATS.

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## Pharmacology

### Receptor Binding and Mechanism of Action

DOPR is a potent full agonist at serotonin 5-HT₂A and 5-HT₂C receptors. Published in vitro data from functional assays (Luethi et al. 2026 [Ref 2], cited via HandWiki [Ref 28]):

- **5-HT₂A receptor:** EC₅₀ = 1.7 nM; Emax = 98.9%
- **5-HT₂C receptor:** EC₅₀ = 0.27 nM
- **5-HT₁ receptors:** Very weak affinity (Ki > 1,000 nM)
- **5-HT₂B receptor:** >25-fold lower potency than 5-HT₂A

**FLAG — data provenance:** The EC₅₀ values cited above are drawn from secondary sources (HandWiki [Ref 28]) citing Luethi et al. 2026 [Ref 2]. The Luethi 2026 paper (PMID 41193673, DOI verified) reports that the 4-propyl compound had the highest in vitro 5-HT₂A potency among the DOx 4-alkyl series, with values in the **1–9 nM range across multiple functional readout assays**. The specific 1.7 nM figure should be verified against the primary Luethi 2026 paper directly at generation.

Among the DOx homologous series (4-methyl, 4-ethyl, 4-propyl, 4-butyl, 4-amyl), DOPR (4-propyl) produced the **highest in vitro 5-HT₂A potencies** across all three functional readouts tested, though shorter and longer chain lengths displayed comparable activities (2–56 nM range across series) (Luethi et al. 2026 [Ref 2]).

**Mechanism:** 5-HT₂A receptor activation is the principal mechanism of psychedelic action, coupling through Gq/G11 proteins to drive phosphoinositide hydrolysis and IP3-mediated intracellular calcium release. Beta-arrestin2 recruitment is also activated. The (R)-enantiomer of DOx amphetamines is expected to have higher intrinsic activity than the (S)-enantiomer at 5-HT₂A receptors (class-level inference from Parrish et al. 2005 [Ref 16] on related phenylisopropylamine DOx compounds). **FLAG:** No DOPR-specific enantioselectivity studies have been published.

Phenylisopropylamine (DOx) analogues have higher intrinsic activity for 5-HT₂A-mediated phosphoinositide hydrolysis than their phenethylamine (2C-X) counterparts (Parrish et al. 2005 [Ref 16]).

Downstream signaling: 5-HT₂A activation by DOPR class agonists regulates BDNF mRNA differentially across brain regions — decreasing expression in hippocampal dentate gyrus granule cells while increasing it in parietal and other neocortical areas, effects blocked by the selective 5-HT₂A antagonist ketanserin (Vaidya et al. 1997 [Ref 13]).

### In Vivo Behavioral Pharmacology (Animal Studies)

**Head-twitch response (HTR) — mouse:**
Noback et al. (2025) [Ref 1] demonstrated that DOPR induces significant HTR in mice at doses ≥0.1 mg/kg. The HTR is a validated proxy for psychedelic-like activity in rodents and is mediated by 5-HT₂A receptor activation (Halberstadt & Geyer 2014 [Ref 25]; Halberstadt & Geyer 2013 [Ref 18]).

Luethi et al. (2026) [Ref 2] placed DOPR among the most potent compounds in the DOx HTR series, with variable maximal HTR counts (23–119) and in vivo potencies (0.42–2.76 mg/kg) across the series, with DOPR and DOM (4-methyl) exhibiting the highest in vivo potency and efficacy respectively.

**Pro-motivational effects at sub-hallucinogenic doses:**
At doses as low as 0.0106 mg/kg (well below the ≥0.1 mg/kg HTR threshold), DOPR significantly improved progressive ratio breakpoint task (PRBT) performance in low-performing mice without affecting high-performing animals (Noback et al. 2025 [Ref 1]). This dose-response separation is central to DOPR's current research interest as a potential therapeutic agent for amotivated states.

**Brain distribution:** DOPR has the highest brain/plasma ratio among DOM homologues in rodents (reported via secondary sources [Ref 28]), suggesting favorable CNS penetration. **FLAG:** Primary citation for this pharmacokinetic claim was not directly verified; treat as provisional pending primary source access.

### Structure-Activity Relationship Context

Oberlender et al. (1995) [Ref 8] established a key SAR finding for the DOx class: the potency of 1-(2,5-dimethoxy-4-alkylphenyl)-2-aminopropane hallucinogens drops dramatically when the 4-alkyl substituent exceeds propyl in length or is branched. This positions DOPR at the **optimum chain length** for the 4-position substitution in this class.

Nichols (2018) [Ref 4] and Glennon & Dukat (2024) [Ref 10] confirm that the 4-position substitution on the 2,5-dimethoxyamphetamine scaffold critically determines both potency and pharmacological character of DOx compounds, with lipophilic substituents at 4-position generally enhancing 5-HT₂A affinity and potency.

The 1977 Nichols, Shulgin & Dyer paper [Ref 9] established the directional lipophilic character of DOx phenethylamines, documenting how lipophilicity of the 4-substituent influences psychotomimetic potency — foundational for understanding why the propyl group represents the potency optimum.

### Pharmacokinetics

**No published human pharmacokinetic studies exist for DOPR.** All pharmacokinetic characterization below is by class inference:

- **Metabolism:** DOx compounds are metabolized primarily via O-demethylation at the 2- and 5-methoxy positions (established for DOC in WHO Critical Review [Ref 19]). DOPR is expected to follow this same pathway. N-deamination via MAO is also likely. The propyl chain at C-4 may undergo beta-oxidation. No published CYP enzyme assignment for DOPR.
- **Blood-brain barrier penetration:** Rodent data indicates effective CNS penetration (highest brain/plasma ratio among DOM homologues) [Ref 28].
- **Duration mechanistic basis:** The exceptionally long duration (20–30 h per Shulgin [Ref 7]) is consistent with the high lipophilicity of the propyl substituent, the alpha-methyl group (which retards MAO-mediated deamination), and high receptor residence time characteristic of DOx agonists.
- **Bioavailability:** Not published. Oral route documented in PiHKAL.
- **Half-life:** Not published.

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## History

DOPR was first documented in the published scientific literature by Alexander Shulgin, reportedly as early as 1970 [Refs 27, 28]. The earliest verifiable co-authored publication is Nichols, Shulgin & Dyer (1977) [Ref 9], which discussed directional lipophilicity of DOx-class phenethylamine psychotomimetics including propyl-substituted analogs.

The compound is documented comprehensively in Shulgin's 1991 book *PiHKAL: Phenethylamines I Have Known and Loved* [Ref 7], entry #71. PiHKAL remains the primary source for human bioassay data, synthesis route, and clinical description.

The broader DOx class was developed through parallel tracks: DOI, DOC, and DOB were first formally synthesized by the Nichols/Glennon groups in 1973 (Glennon & Dukat 2024 [Ref 10]); DOPR's provenance is distinctly Shulgin's own laboratory.

DOPR received virtually no research attention for decades after PiHKAL's publication. A major shift occurred with the 2025 Noback et al. study [Ref 1], which identified DOPR's ability to enhance motivation at sub-hallucinogenic doses in rodents — positioning it as a candidate tool compound for therapeutic development. The same year, Luethi et al. (2026 [Ref 2]) published a systematic comparison of the DOx 4-alkyl series in which DOPR emerged as the in vitro 5-HT₂A potency leader.

**FLAG:** The claim that Shulgin "first described" DOPR in 1970 is widely stated in secondary sources [Refs 27, 28] but the specific 1970 publication could not be identified or verified through PubMed or OpenAlex searches. The earliest PubMed-verifiable co-authored Shulgin paper on DOx compounds is from 1977 [Ref 9]. Generation agent should note this gap.

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## Subjective Effects

Published subjective effect data is exclusively from Shulgin's self-experimental bioassays documented in PiHKAL [Ref 7]. No controlled human studies have been conducted.

**From PiHKAL entry #71 [Ref 7]:**
- **Dose range:** 2.5–5.0 mg orally
- **Onset:** Very slow — threshold effects appear approximately 90 minutes post-ingestion
- **Duration:** 20–30 hours (exceptionally long for a psychedelic)
- **Character:** "Drifting into that place that lies between a not-quite-awake and a not-quite-asleep state" at threshold doses
- **Visual effects:** Prominent visual phenomena reported at moderate doses — closed-eye imagery, visual phenomena at lower doses; "heavy duty" unavoidable visuals at higher doses [Ref 28]
- **Higher doses (5 mg):** Intense psychedelic effects lasting into the following day, with lingering baseline shifts
- **Sleep disruption:** Insomnia and sleep disruption documented

**Comparison compound note:** Shulgin documented that DOIP (the isopropyl analog) was 1–2 orders of magnitude **less potent** than DOPR — establishing DOPR as the more potent of the two propyl-variant analogs.

**No controlled human studies exist.** All human effect data is from self-experimental bioassays (Shulgin, uncontrolled, N=small). This is a significant evidence gap.

**Effects taxonomy inference (class-level, not substance-specific unless noted):**
Based on the DOx class profile and PiHKAL data, likely domains include:
- **Perception:** geometry, visual drifting, visual morphing, color alteration, color enhancement, tracers, internal hallucinations, external hallucinations (at higher doses), light sensitivity, synesthesia
- **Cognition:** thought connectivity, conceptual thinking, analysis enhancement, creativity enhancement, pattern recognition enhancement
- **Feeling:** emotional enhancement, euphoria (variable)
- **Body:** stimulation, wakefulness (consequent to insomnia), muscle tension (class-level DOx inference), vasoconstriction (class-level inference)
- **Time:** time alteration
All effect claims beyond Shulgin's bioassay data are class-level inferences and require flagging.

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## Safety & Toxicity

### DOPR-Specific Data

**No published human case reports of adverse events, overdose, or fatalities specific to DOPR have been identified.** This is a significant gap.

**No LD₅₀ data for DOPR exists in published literature.**

**No long-term safety studies exist.**

### Class-Level Safety Inference (DOx compounds)

Based on the WHO Critical Review of DOC [Ref 19] and Halberstadt (2017 [Ref 26]) on related 5-HT₂A agonists, the DOx class is associated with the following adverse events in cases of toxicity:

- Agitation, aggressive behaviour
- Hallucinations (prolonged, potentially unavoidable)
- Tachycardia
- Rhabdomyolysis (particularly in severe cases with agitation/hyperthermia)
- Seizures
- Hyperthermia
- Some features persisting for up to 33 hours (consistent with DOPR's duration profile)

**FLAG:** All adverse event data is inferred from structurally related DOx compounds. No DOPR-specific case reports have been published.

### Cardiovascular Concern

Glennon & Dukat (2024 [Ref 10]) and secondary analyses (VCU thesis data [cited in Ref 15]) note a high correlation between DOx compound affinities at 5-HT₂A and 5-HT₂B receptors. Chronic 5-HT₂B agonism is associated with cardiac valvulopathy (fenfluramine precedent). DOPR's 5-HT₂B activity is reported as >25-fold lower potency than 5-HT₂A [Ref 28], but this remains a theoretical concern for repeated use. **FLAG: No human cardiac safety data for DOPR.**

### Duration as a Safety Consideration

The 20–30 hour duration represents a distinct harm profile: prolonged exposure to psychedelic effects, extreme sleep deprivation, sustained cardiovascular stimulation, and extended vulnerability to adverse psychological states. This is substantially longer than LSD (~12 h) or psilocybin (~6 h).

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## Harm Reduction

No published harm reduction guidelines specific to DOPR exist. The following is derived from class-level evidence and the substance's known pharmacological and duration profile.

**Testing:** DOPR is a DOx compound. Ehrlich reagent: expected to produce no colour reaction (DOx compounds are negative with Ehrlich). Marquis reagent: expected to produce black/dark reaction. Mecke: expected to react. Reagent test specificity is insufficient to distinguish between DOx compounds or confirm DOPR identity — mass spectrometry required for definitive identification. **FLAG:** No published colorimetric reagent validation data specific to DOPR identified.

**Dose precision:** Given the narrow dose range (2.5–5 mg) and exceptional duration (20–30 h), milligram-accurate dosing is critical. Powder on blotter is potentially hazardous due to dose uncertainty.

**Set and setting:** The prolonged duration requires careful planning; effects may extend across sleep periods.

**Emergency response:** No published DOPR-specific emergency protocols. General 5-HT₂A agonist overdose management applicable (calm environment, sedation with benzodiazepines if required, supportive care; antipsychotics such as haloperidol have been used in DOx class toxicity, and ketanserin/volinanserin as 5-HT₂A antagonists in emergency contexts — class inference).

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## Tolerance & Dependence

### Tolerance

**No DOPR-specific tolerance data published.** Class-level inference from the DOx/hallucinogen class:

Behavioral tolerance to psychedelics is established and rapid. Gresch et al. (2005 [Ref 22]) demonstrated in rats that chronic LSD treatment (5 days) produced 44% reduction in LSD discriminative stimulus effects, associated with reduced 5-HT₂A receptor density and GTPgammaS coupling in medial PFC and anterior cingulate cortex. The DOx compound [¹²⁵I]DOI showed similarly reduced stimulation in cortical regions after chronic LSD, mediated via 5-HT₂A (not 5-HT₂C) receptor downregulation.

**Cross-tolerance:** DOx class compounds are expected to show cross-tolerance with other 5-HT₂A agonist psychedelics (LSD, psilocybin, mescaline) based on shared mechanism (class inference; Winter 2008 [Ref 24]).

Conventional guidance suggests a washout of 3–5 days between high psychedelic doses for tolerance to reset. Given DOPR's extreme duration, longer intervals may be appropriate.

### Dependence

**No evidence of physical dependence or withdrawal syndrome for DOPR or the DOx class.** The WHO Critical Review of DOC [Ref 19] explicitly states: "Dependence potential in humans or animals has not been demonstrated." This is consistent with the general literature showing psychedelics do not produce classic reward/reinforcement patterns or withdrawal syndromes (Inserra et al. 2021 [Ref 14]).

No self-administration data for DOPR exists.

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## Interactions

**No DOPR-specific drug interaction studies have been published.** All interaction data is class-level inference.

### Serotonergic Interactions
Malcolm & Thomas (2022 [Ref 12]) reviewed serotonin toxicity risk for serotonergic psychedelics combined with SSRIs and MAOIs:
- **SSRIs/SNRIs:** May attenuate DOPR effects via 5-HT₂A receptor downregulation with chronic use; acute SSRI co-administration may also attenuate effects. Serotonin syndrome risk is theoretically elevated but poorly characterized for DOx-class compounds specifically.
- **MAOIs:** Contraindicated class-level. MAO inhibition may increase duration and intensity of DOx effects by blocking N-deamination; acute serotonin syndrome risk.
- **mGlu2/3 receptor agonists:** Halberstadt et al. (2019 [Ref 29]) demonstrated that chronic mGlu2/3 agonist treatment diminishes behavioral responses to 5-HT₂A agonist phenethylamines, suggesting a pharmacological interaction pathway.
- **Lithium:** Contraindicated (class-level inference; lowers seizure threshold; serotonin syndrome risk in combination with psychedelics).

### Stimulant/Cardiovascular Interactions
DOPR is an amphetamine derivative. Co-administration with other stimulants (amphetamines, MDMA, cocaine) would be expected to compound cardiovascular load. No published data.

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## Legal Status

### United States
DOPR is **not explicitly named** in the Controlled Substances Act. DOM (2,5-dimethoxy-4-methylamphetamine) is a Schedule I controlled substance. DOPR is a structural analog of DOM and may be subject to the **Federal Analogue Act (FAA)** if intended for human consumption — the FAA treats close analogs of Schedule I/II substances as Schedule I substances for purposes of manufacture, distribution, or possession with intent to distribute for human use. The legal term "substantially similar" has been contested in courts. DOPR is sold by chemical suppliers (Cayman Chemical [Ref 20]) as an analytical reference standard with no explicit human consumption marketing.

### Canada
DOPR is a **controlled substance in Canada** under Schedule III of the Controlled Drugs and Substances Act, via broad phenethylamine blanket-ban language [Ref 28].

### United Kingdom
DOPR is covered by the **Psychoactive Substances Act 2016**, which prohibits the production, supply, and importation of all psychoactive substances not otherwise exempted (food, alcohol, tobacco, licensed medicines). DOPR has no medicinal exemption. Additionally, UK chemical suppliers list DOPR as requiring a UK Home Office licence [Ref 28], suggesting it may also carry a licence requirement under the Misuse of Drugs Act 1971 framework, or suppliers apply precautionary licensing. **FLAG:** Specific scheduling class under the MDA 1971 for DOPR was not confirmed in publicly accessible legislative databases.

### European Union / International
DOPR is **not scheduled under the 1961, 1971, or 1988 United Nations drug conventions** (consistent with the status of DOC, which also lacks international scheduling [Ref 19]). Individual EU member state laws vary; several countries have broader analogue scheduling laws.

### Australia
No specific scheduling information for DOPR under the Therapeutic Goods Administration Poisons Standard (SUSMP) was identified in available sources. Australian state analogue provisions may apply. **FLAG: Australian legal status unresolved.**

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## Clinical Trials

**No clinical trials for DOPR are registered on ClinicalTrials.gov.** A search of ClinicalTrials.gov for "DOPR" and "2,5-dimethoxy-4-propylamphetamine" returned zero results [research step 11].

DOPR is a pre-clinical stage compound only. The Noback et al. 2025 study [Ref 1] calls for further investigation in rodent disease models as a precondition to human research.

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## Community Feedback Analysis

No community feedback submitted for DOPR (Part A2 is empty).

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## Gaps & Flags

### Critical Data Gaps

1. **No published human pharmacokinetic data:** Tmax, Cmax, half-life, bioavailability, volume of distribution, CYP enzyme assignment, and metabolite identification are entirely absent for DOPR. Duration (20–30 h) is from a single self-experimental report (Shulgin).

2. **No human controlled studies:** All human effect data derives from Shulgin's uncontrolled self-bioassays (PiHKAL [Ref 7]). Sample size and methodological rigor are unknown.

3. **No published adverse event or case report data specific to DOPR:** The safety profile rests entirely on class-level extrapolation from DOx analogs (DOC, DOI, DOB).

4. **No LD₅₀ data published** for DOPR in any species.

5. **DOPR-specific enantioselectivity data absent:** (R)- vs. (S)-DOPR activity comparison is a class inference only [Ref 16].

6. **Specific CAS/metabolism data:** O-demethylation pathway assumed from DOC class data but not confirmed experimentally for DOPR.

7. **"First described 1970" claim:** Secondary sources state Shulgin first described DOPR in 1970, but the specific 1970 publication was not identified. The earliest verifiable co-authored Shulgin paper mentioning DOx propyl character is 1977 [Ref 9]. PiHKAL (1991) [Ref 7] is the primary verifiable source.

### Safety-Critical Flags

8. **FLAG — dose range:** The PiHKAL dose of 2.5–5 mg is the only published human dose data. It is from self-experiment (Shulgin; N unspecified) and has not been confirmed in any controlled setting. **This safety-critical value requires flagging at generation.**

9. **FLAG — duration:** 20–30 hours is from Shulgin self-report only. No replicated human data. The extreme duration is consistent with rodent pharmacokinetics (Luethi 2026 [Ref 2]) but has not been confirmed in a controlled human study.

10. **FLAG — EC₅₀ values (5-HT₂A: 1.7 nM):** Cited via HandWiki [Ref 28] citing Luethi et al. 2026 [Ref 2]. The Luethi 2026 paper abstract confirms 1–9 nM range. Specific 1.7 nM value should be verified against primary tables in Luethi 2026 before use as a precise pharmacological claim.

11. **FLAG — brain/plasma ratio claim:** "Highest brain/plasma ratio among DOM homologues" cited via secondary source [Ref 28]. Primary data from Luethi 2026 [Ref 2] was not fully accessible; should be verified at generation.

12. **FLAG — UK MDA scheduling class:** Supplier licensing requirement implies regulatory classification but the specific MDA 1971 schedule (A, B, or C) for DOPR, if any, was not confirmed from legislative text.

13. **FLAG — 5-HT₂B cardiac risk:** Class-level concern; no human cardiac data for DOPR exists. Should be noted in article but framed as theoretical.

14. **FLAG — Australia legal status:** Not resolved; classified as unresolved.