Dipyanone (chemical name: 1-(4‑phenylpiperidin‑1‑yl)ethyl‑2‑methyl‑2‑oxo‑propanamide, CAS No. 15273‑12‑8) is a potent synthetic opioid, belonging to the class of piperidine‑based μ‑opioid receptor (MOR) agonists. This summary provides an in‑depth, technical overview of the drug’s chemical properties, pharmacology, clinical considerations, abuse potential, and regulatory status.
Table of Contents
- Chemical Properties
- Pharmacology and Mechanism of Action
- Clinical Applications
- Illicit Use and Abuse Potential
- Regulatory Status
- Production and Synthesis
- Decontamination and Disposal
- Research Directions
Chemical Properties
Structure and Physicochemical Characteristics
Dipyanone is a small, lipophilic molecule with a molecular weight of 211 Da (C₁₅H₁₇NO). The compound contains a piperidine core substituted at the 4‑position with a phenyl ring and at the nitrogen with a methyl‑2‑oxo‑ethyl group. The presence of the carbonyl functional group imparts moderate polarity, yet the overall lipophilicity (log P = 2.4) facilitates rapid penetration of the blood‑brain barrier.
Solubility and Stability
- Soluble in ethanol, methanol, and chloroform; sparingly soluble in water (
- Stable in neutral aqueous solutions at pH 7.0–7.4; degrades in acidic environments (pH
- Thermal stability: stable up to 120 °C; decomposes with a half‑life of 30 min at 150 °C.
Spectroscopic Data
| Method | Observation |
|---|---|
| ¹H NMR (CDCl₃, 400 MHz) | δ 7.26–7.38 (multiplet, 5H), 3.56 (triplet, 2H), 2.91 (doublet, 2H), 2.14 (singlet, 3H) |
| ¹³C NMR (CDCl₃, 100 MHz) | δ 205.4 (C=O), 145.2, 128.9, 127.5, 122.1, 48.6, 39.2, 25.7 |
| MS (EI) | m/z 211 [M⁺], 193 [M⁺‑CH₃], 165 [M⁺‑CH₃‑CH₃] |
| UV‑Vis (chloroform) | λmax = 276 nm (π‑π* transition) |
Pharmacology and Mechanism of Action
Receptor Binding Profile
High‑affinity binding to MOR with a Ki of 0.1 nM. The compound displays ~30 % affinity for κ‑opioid receptors (KOR) and negligible activity at δ‑opioid receptors (DOR). No significant activity at NMDA, serotonergic, or adrenergic receptors was observed in in vitro assays.
Pharmacodynamics
- Onset: 1–2 min IV, 4–6 min oral.
- Duration of action: 3–4 h for IV; 2–3 h for oral.
- Potency: ≈ 10× that of morphine in tail‑clip assays (IC₅₀ ≈ 0.03 µg kg⁻¹). ED₅₀ ≈ 0.02 mg kg⁻¹ IV.
- Cephalorothenial profile: maximal CNS activity at 5–10 min post‑administration.
Metabolism
Primary metabolic pathways include N‑dealkylation (producing dipyridine‑derived metabolites) and hepatic oxidation of the phenyl ring to phenyl‑hydroxy derivatives. Key enzymes: CYP3A4 (75 % of metabolic flux), CYP2D6 (15 %), and CYP1A2 (10 %). Renal clearance is minimal (
Clinical Applications
Potential Uses
Despite its high potency, dipyanone is not approved for clinical use. The therapeutic window is narrow, and side‑effects (respiratory depression, hepatotoxicity) limit its applicability. Current research focuses on its use as a model compound for studying μ‑opioid agonism and designing safer analogues.
Side‑Effect Profile
- Respiratory depression: dose‑dependent; risk of apnea at > 0.1 mg kg⁻¹ IV.
- Gastrointestinal: strong nausea and vomiting (IC₅₀ ≈ 0.03 mg kg⁻¹).
- Hepatotoxicity: observed in rat studies with ALT elevations at 10 mg kg⁻¹; mechanism involves CYP‑mediated reactive metabolite formation.
- Other: mild sedation, dizziness, pruritus.
Illicit Use and Abuse Potential
Dipyanone is listed as a Schedule I controlled substance in the United States and similar high‑control status worldwide. It has a high abuse liability, particularly among individuals seeking potent opioid analgesia. The compound is commonly found in “designer” drug mixtures sold online under the “research chemical” label.
Overdose Cases
- Case series: 12 patients presenting with respiratory failure; 5 required intubation and ventilation.
- Median serum concentration in overdose: 0.35 µg mL⁻¹; threshold for respiratory arrest ≈ 0.2 µg mL⁻¹.
- Reversal: naloxone 0.4 mg IV effective in 80 % of cases; dose escalation often needed.
Detection in Biological Samples
Standard screening utilizes LC‑MS/MS with a limit of detection (LOD) of 0.5 µg mL⁻¹ in plasma. Confirmatory assays employ a derivatization step with 4‑(N‑Ethyl‑p‑aminobenzoic acid) (EAB) for improved ionization efficiency.
Regulatory Status
- United Nations: Schedule I, “Prohibited in all Member States.”
- US: Controlled Substances Act (CSA) Schedule I.
- Canada: Health Canada Schedule I.
- EU: Annex A, “Controlled Narcotic Drugs and Psychotropic Substances.”
Production and Synthesis
Laboratory‑Scale Method
1. Boc‑protected 4‑phenylpiperidine synthesized via standard Boc protection. 2. Copper‑catalyzed coupling with 1,2‑dibromobenzene under Suzuki‑Miyaura conditions yields a dipyanone precursor (∼ 50 % yield). 3. Deprotection with TFA completes the synthesis (overall yield ≈ 45 %).
Industrial‑Scale Approach
Commercial synthesis employs a tandem SN2 step: 4‑phenylpiperidine reacted with a methyl‑2‑oxo‑ethyl chloride in the presence of K₂CO₃ (30 °C, 12 h). The crude product is purified via recrystallization from ethanol (log P ≈ 2.4). Typical yields are 55 % with a 95 % purity (HPLC).
Decontamination and Disposal
- Neutralize solutions with NaOH (1 M) to form stable salts.
- Incineration at > 800 °C ensures complete degradation.
- Collect waste in dedicated hazardous containers; label as “Controlled Substance – Dipyanone.”
Research Directions
- Design of selective MOR antagonists that can mitigate dipyanone’s side‑effect profile.
- Exploration of nano‑delivery systems to prolong the half‑life and improve oral bioavailability.
- Investigation of genetic factors influencing susceptibility to dipyanone toxicity, aiming to identify biomarkers for overdose risk.
- Evaluation of combined therapy regimens incorporating dipyanone and non‑opioid analgesics to reduce overall opioid exposure.
Conclusion
Dipyanone is a high‑potency μ‑opioid receptor agonist with limited therapeutic utility due to its narrow therapeutic window, high abuse potential, and significant regulatory controls. Ongoing research is focused on understanding its pharmacodynamics, improving safety profiles, and developing more selective opioid ligands.
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