(D-Pen2,D-Pen5)-Enkephalin

The peptide known as (D-Pen2,D-Pen5)-Enkephalin is a synthetic analog of the naturally occurring enkephalins, which are endogenous opioid peptides. This particular compound has garnered significant attention due to its high affinity and selectivity for the delta opioid receptors, which are implicated in a variety of physiological processes including pain modulation, mood regulation, and neuroprotection126. The unique structure of (D-Pen2,D-Pen5)-Enkephalin, featuring D-penicillamine at positions 2 and 5, contributes to its pharmacological profile and has made it a subject of interest in opioid research.

(D-Pen2,D-Pen5)-Enkephalin binds with high affinity to delta opioid receptors, as evidenced by its low nanomolar Kd values in both rat brain and NG 108-15 cell membranes1. The binding characteristics of this ligand have been thoroughly investigated, revealing that it is not significantly displaced by mu receptor-selective agonists, thus confirming its selectivity for the delta receptor subtype23. The presence of 3-methyl groups in the D-Pen2 residue of the peptide has been shown to influence its receptor selectivity, with steric interactions playing a role in its lower affinity for mu receptors6. Furthermore, the conformational flexibility of the peptide has been studied, indicating that its cyclic nature may not be as rigid as previously thought, with solvent effects potentially influencing its bioactive conformation5.

Neuropharmacology

In neuropharmacology, (D-Pen2,D-Pen5)-Enkephalin's selective delta receptor agonism has been exploited to study receptor binding characteristics and the regional distribution of these receptors in the brain12. Its high selectivity makes it an excellent tool for distinguishing delta from mu receptor-mediated effects in various experimental models.

Neurotoxicology

Interestingly, (D-Pen2,D-Pen5)-Enkephalin has been found to reduce the endogenous aluminum content in the rat central nervous system, suggesting a potential role in neurotoxicology and the mitigation of metal-induced neurotoxicity4. This effect was dose-dependent and could be reversed by naloxone, an opioid receptor antagonist, further underscoring the involvement of delta opioid receptors in this process.

Structural Biology

The compound has also been valuable in structural biology, where its conformational properties have been analyzed through extensive computational methods. These studies have provided insights into the flexibility and solution conformation of cyclic opioid peptides, which are crucial for understanding their interactions with receptors5.

Medicinal Chemistry

In medicinal chemistry, the structure-activity relationships of (D-Pen2,D-Pen5)-Enkephalin analogs have been explored to dissect the contributions of specific methyl groups to receptor binding affinity and selectivity6. Such investigations are fundamental for the design of new therapeutic agents targeting opioid receptors with improved efficacy and reduced side effects.