DADLE
Also known as: [D-Ala2, D-Leu5]-Enkephalin, [D-Ala2, D-Leu5]enkephalin, 63631-40-3, D-Ala(2)-Leu(5)-Enkephalin, DADLE, Tyr-D-Ala-Gly-Phe-D-Leu
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Summary
DADLE ([D-Ala2, D-Leu5]-enkephalin) is a synthetic peptide that selectively activates delta‑opioid receptors (DORs). In preclinical research it has been investigated as a neuroprotective and organ‑preserving agent for conditions such as stroke, traumatic brain injury, hemorrhagic shock, and neurodegenerative models. The peptide also induces pharmacological hypothermia, a state resembling natural hibernation, which may contribute to its protective effects. DADLE remains a research‑only compound and has not been approved for clinical use.
Mechanism of Action
DADLE binds to delta‑opioid receptors, a G‑protein‑coupled receptor family widely expressed in the brain and peripheral tissues. Receptor activation stabilises ionic homeostasis, initiates intracellular survival cascades, and suppresses pro‑apoptotic signalling. In neuronal models DADLE reduces expression of tumor‑necrosis‑factor‑related p53 and the immediate‑early gene c‑fos, attenuating inflammation and apoptosis. The same DOR activation also triggers a metabolic shift that lowers core temperature, mimicking hibernation and further limiting ischemic injury.
What the Research Shows
Preclinical studies reported in several reviews show that DADLE protects neurons and glia from ischemia‑reperfusion injury, reduces dopaminergic terminal loss after methamphetamine exposure, and enhances survival of transplanted dopaminergic cells in Parkinsonian rats. In models of hemorrhagic shock, DADLE contributed to improved tissue perfusion and reduced inflammatory damage. The peptide also prolongs viability of isolated organs (lung, heart, liver, kidney) and can induce a hibernation‑like hypothermic state that augments neuroprotection after traumatic brain injury and stroke. All evidence derives from cell culture, rodent, or ex‑vivo organ studies; no human trials have been reported.
Reported Benefits
Animal and cellular data suggest DADLE can increase cell viability under stress, limit neuronal death after ischemic or toxic insults, and improve graft survival in Parkinsonian models. Its ability to induce controlled hypothermia offers a non‑mechanical route to neuroprotection. Additionally, organ‑preservation studies indicate potential utility in transplantation or trauma settings. These benefits are observed across multiple delivery routes in experimental settings.
Limitations of the Evidence
The supportive data are limited to preclinical models; no clinical efficacy or safety data exist. Translational gaps include optimal dosing, timing, and route of administration for humans. Potential opioid‑related side effects have not been characterised in the cited literature. Moreover, the majority of findings are from acute injury models, and long‑term outcomes remain unclear.
Safety Considerations
Published abstracts do not report adverse events for DADLE, but as a delta‑opioid receptor agonist it may share class‑related risks such as respiratory depression, sedation, or tolerance at high doses. The peptide’s effects appear reversible by naloxone or naltrexone, indicating opioid specificity. Until systematic toxicology studies are performed, caution is advised when extrapolating to human use.
How It Is Administered
Research investigations have administered DADLE via intracerebroventricular, intrathecal, intravenous, and subcutaneous routes. Formulations are typically aqueous peptide solutions suitable for injection. The choice of route depends on the target tissue and experimental design; no standardized clinical formulation exists.
Routes of Administration
Goals & Uses
- NeuroprotectionNeurologyLow
- Cardioprotection / ischemia-reperfusion injuryCardiovascularModerate
- AntinociceptionResearch / AnalgesiaModerate
- Organ preservationResearch / TransplantationLow
- Induction of hibernation-like stateResearch / Suspended AnimationLow
- Opioid receptor pharmacology toolResearch / Receptor CharacterizationHigh
- AnalgesiaPain ManagementModerate
Contraindications
- concomitant CNS depressantsPharmacologicModerate
- Human therapeutic useRegulatory/safetyHigh
- Respiratory compromiseClinical (preclinical Extrapolation)High
Adverse Effects
- Cardiovascular depressionCardiovascularUncommon
- Tolerance developmentPharmacologicalUncommon
- Respiratory depressionRespiratoryCommon
- Sedation / CNS depressionNeurologicalCommon
- SedationCNSCommon
- Tolerance and dependencePharmacologicalUnknown
Drug Interactions
- CNS depressantsHigh
- BenzodiazepinesLow
- other opioids (e.g., morphine)Moderate
- Naloxone / NaltrexoneLow
Population Constraints
- Humans (general)Regulatory / SafetyAbsolute
- human clinical useClinicalAbsolute
- Pregnant animalsReproductiveRelative
Regulatory Status
- European UnionUnapprovedNo marketing authorization; used in pre‑clinical studies.
- United StatesUnapprovedInvestigational research chemical; not scheduled as a controlled substance but used under institutional review.
- United KingdomUnapprovedClassed as a research peptide; not for therapeutic use.
No approved medical indication; classified as an investigational research compound in most jurisdictions.
Evidence & Sources
- Journal ArticleModerateLee JY, et al.2018-01-01T00:00:00.000000Z
- Journal ArticleModerateSu TP2000-01-01T00:00:00.000000Z
- Journal ArticleModerateWolf A, Lusczek ER, Beilman GJ2018-01-01T00:00:00.000000Z
- Journal ArticleModerateDeschamps JR, George C, Flippen-Anderson JL1996-01-01T00:00:00.000000Z
- Journal ArticleModerateLiska MG, et al.2018-01-01T00:00:00.000000Z
- Journal ArticleModerateBorlongan CV, Wang Y, Su TP2004-01-01T00:00:00.000000Z
Frequently Asked Questions
What type of molecule is DADLE?
DADLE is a synthetic dipeptide analogue of enkephalin that selectively activates delta‑opioid receptors, making it an opioid peptide agonist used in laboratory studies.
Has DADLE been tested in humans?
No. All published evidence involves cell cultures, rodent models, or isolated organ preparations. The compound has not been evaluated in clinical trials and is not approved for any medical indication.
How does DADLE protect the brain after injury?
By stimulating delta‑opioid receptors, DADLE stabilises ion balance, suppresses pro‑apoptotic genes (e.g., p53, c‑fos), reduces inflammation, and can lower body temperature, together limiting neuronal death after ischemia or toxic insults.
Can DADLE be used to preserve organs for transplantation?
Preclinical studies report that DADLE prolongs the viability of isolated lungs, heart, liver, and kidney tissue, suggesting a potential role in organ preservation, though no human data are available.
What are the known side effects of DADLE?
Side‑effect information is not provided in the cited literature. As a delta‑opioid agonist, it could theoretically cause opioid‑type effects such as sedation or respiratory depression, but this remains untested.
What is DADLE?
DADLE ([D-Ala2, D-Leu5]-enkephalin) is a synthetic peptide that selectively activates delta‑opioid receptors (DORs). In preclinical research it has been investigated as a neuroprotective and organ‑preserving agent for conditions such as stroke, traumatic brain injury, hemorrhagic shock, and neurodegenerative models. The peptide also induces pharmacological hypothermia, a state resembling natural hibernation, which may contribute to its protective effects. DADLE remains a research‑only compound and has not been approved for clinical use.
What is DADLE used for?
DADLE is educationally associated with: Neuroprotection, Cardioprotection / ischemia-reperfusion injury, Antinociception, Organ preservation, Induction of hibernation-like state, Opioid receptor pharmacology tool, Analgesia. Educational only — not medical advice.
How is DADLE administered?
Recorded routes of administration: Intracerebroventricular, Intrathecal, Intravenous, Subcutaneous.
What are the potential side effects of DADLE?
Reported adverse effects include: Cardiovascular depression, Tolerance development, Respiratory depression, Sedation / CNS depression, Sedation, Tolerance and dependence. This list is not exhaustive — consult a qualified clinician.
Who should avoid DADLE?
Recorded contraindications: concomitant CNS depressants, Human therapeutic use, Respiratory compromise. Consult a qualified clinician before use.