Description

Product Description

[D-Ala²]Leucine-enkephalin is a synthetic pentapeptide and a stable analog of the endogenous opioid peptide Leu-enkephalin. By substituting the second amino acid residue with D-alanine, this analog resists enzymatic degradation, leading to prolonged biological activity and greater selectivity toward the delta opioid receptor (DOR). The compound has become a cornerstone in neuropharmacological research, particularly in the study of pain modulation, receptor binding, and neuronal signaling pathways.

Leu-enkephalin, one of the two major enkephalins found in the mammalian central nervous system, plays an essential role in modulating nociceptive transmission, stress response, and emotional regulation. However, native enkephalins are rapidly degraded by peptidases such as enkephalinase and aminopeptidase, which severely limits their in vivo utility. [D-Ala²]Leucine-enkephalin overcomes this limitation by incorporating a D-alanine residue that resists enzymatic cleavage, resulting in a long-acting delta-selective opioid peptide.

This peptide’s structure enables it to bind efficiently to delta receptors while minimizing interaction with mu and kappa opioid receptors. Such receptor specificity allows researchers to dissect the complex signaling mechanisms of endogenous opioid systems without confounding cross-reactivity. Studies employing [D-Ala²]Leucine-enkephalin have helped elucidate the delta receptor’s role in neuroprotection, mood regulation, and immune modulation.

Beyond analgesic signaling, [D-Ala²]Leucine-enkephalin also provides valuable insights into intracellular signaling cascades, including G-protein coupling, cAMP inhibition, and β-arrestin recruitment. These mechanisms are pivotal in understanding biased agonism and receptor desensitization — phenomena increasingly recognized as key determinants of drug efficacy and tolerance.

In addition, the compound has been used to study neuroendocrine regulation, cardiovascular control, and stress responses. The peptide’s stability and receptor selectivity make it a reliable model compound for developing novel delta agonists and investigating opioid receptor heterodimerization, a process thought to influence receptor trafficking and pharmacological profiles.

In the context of pain modulation research, [D-Ala²]Leucine-enkephalin demonstrates both central and peripheral activity. In animal models, it induces potent analgesia through spinal and supraspinal pathways, with a significantly prolonged half-life compared to Leu-enkephalin. Researchers have used it to differentiate delta receptor-mediated antinociceptive responses from mu receptor-driven mechanisms, further clarifying the distinct physiological roles of opioid receptor subtypes.

Moreover, emerging studies suggest that delta opioid receptor agonists may have neuroprotective and mood-enhancing effects, potentially linked to their modulation of calcium homeostasis, oxidative stress responses, and mitochondrial signaling. [D-Ala²]Leucine-enkephalin serves as a valuable experimental tool for these investigations, enabling exploration of receptor-mediated pathways involved in neuroplasticity and resilience to stress.

Its synthetic nature also facilitates chemical modifications, enabling structure–activity relationship (SAR) studies aimed at enhancing receptor selectivity, bioavailability, and blood–brain barrier permeability. For peptide chemists, this compound exemplifies a rationally designed opioid ligand that maintains physiological relevance while offering superior stability for controlled laboratory applications.

Product Specifications

Mechanism of Action

[D-Ala²]Leucine-enkephalin functions primarily as a delta opioid receptor (DOR) agonist. The delta receptor is a G-protein–coupled receptor (GPCR) that modulates neuronal excitability and neurotransmitter release through the inhibition of adenylyl cyclase and subsequent reduction of intracellular cAMP levels. Upon binding to the DOR, [D-Ala²]Leucine-enkephalin initiates a conformational change in the receptor that activates the Gi/o family of G-proteins, leading to downstream effects including decreased calcium influx and enhanced potassium efflux — both of which hyperpolarize neurons and reduce neurotransmitter release.

This mechanism underlies its ability to suppress nociceptive transmission in the spinal cord and brainstem, producing analgesic-like responses in experimental models. However, unlike mu receptor agonists, delta-selective ligands such as [D-Ala²]Leucine-enkephalin tend to produce minimal respiratory depression or dependency, making them valuable tools for exploring the therapeutic window of opioid receptor pharmacology.

At the molecular level, activation of DORs by [D-Ala²]Leucine-enkephalin results in modulation of MAPK/ERK and PI3K/Akt pathways, which are associated with neuronal survival, anti-apoptotic signaling, and neurogenesis. This downstream signaling diversity contributes to growing interest in delta agonists as neuroprotective agents.

Furthermore, this peptide has been observed to modulate the release of neurotransmitters such as dopamine, serotonin, and acetylcholine, implying potential roles in mood regulation, reward processing, and learning. The selective stimulation of delta receptors in limbic structures such as the nucleus accumbens and amygdala has been linked to anxiolytic and antidepressant-like responses in preclinical studies.

[D-Ala²]Leucine-enkephalin’s D-amino acid substitution at position 2 protects it from enzymatic cleavage by aminopeptidases and endopeptidases, enhancing its half-life and receptor occupancy. This biochemical resilience makes it particularly useful in in vivo and in vitro assays where native enkephalins would otherwise be rapidly degraded.

Overall, [D-Ala²]Leucine-enkephalin serves as an exemplary model to study delta receptor–mediated G-protein coupling, biased agonism, and signal transduction kinetics, advancing the understanding of how structural modifications influence receptor behavior and downstream signaling.

Side Effects

While [D-Ala²]Leucine-enkephalin is intended strictly for research use and not for human or veterinary administration, experimental data indicate several potential physiological effects at high concentrations or prolonged exposure. In animal studies, excessive activation of delta opioid receptors can lead to tolerance or desensitization, characterized by diminished receptor responsiveness following continuous stimulation.

In cellular models, overactivation of G-protein signaling may disrupt calcium balance or alter synaptic transmission. However, compared with mu receptor agonists, delta-selective peptides exhibit significantly fewer adverse systemic responses such as respiratory depression, sedation, or constipation.

Possible side effects observed in preclinical contexts include mild hypotension, bradycardia, and transient changes in locomotor activity. Some evidence also suggests that chronic delta receptor stimulation may induce adaptive changes in receptor trafficking and gene expression, potentially influencing long-term neuronal excitability.

Importantly, all studies using [D-Ala²]Leucine-enkephalin should adhere to biosafety and institutional guidelines, ensuring peptide handling and dosing are confined to controlled laboratory conditions. No data support its safety or efficacy for clinical or therapeutic use.

Keywords

[D-Ala²]Leucine-enkephalin, CAS 64963-01-5, delta opioid agonist, Leu-enkephalin analog, pain modulation peptide, neuropharmacology research, GPCR signaling, DOR ligand, biased agonism, neuroscience peptide supplier.

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Disclaimer

All products listed are intended for laboratory research use only and not for human or veterinary use. They are not drugs, medical devices, or diagnostics and should not be administered to humans or animals. Researchers must handle all materials in accordance with institutional biosafety and chemical safety guidelines. The information provided is for scientific reference only and does not imply therapeutic efficacy, safety, or regulatory approval.