88373-73-3

Usage

Uses

Used in Pharmaceutical Research:
DPDPE is used as a research compound for studying the pharmacodynamics and pharmacokinetics of delta-opioid receptor agonists. Its high selectivity for the delta-opioid receptor makes it an ideal tool for investigating the role of this receptor in pain perception and other physiological processes.
Used in Pain Management:
DPDPE is used as an analgesic agent for the management of severe pain. Its potent and selective action on the delta-opioid receptor contributes to its efficacy in providing pain relief, particularly in cases where other opioids may be less effective or have undesirable side effects.
Used in Neurobiological Research:
DPDPE is used as a research tool in neurobiological studies, particularly in investigations of the ventral tegmental area (VTA) and its role in opiate self-administration and addiction. The use of DPDPE in male Long-Evans rats has provided valuable insights into the neural mechanisms underlying opioid addiction and self-administration behaviors.
Used in Drug Delivery Systems:
DPDPE has been studied in conjunction with polyethylene glycol (PEG) conjugates to improve its pharmacokinetic properties, such as solubility, stability, and bioavailability. This research aims to develop more effective drug delivery systems for DPDPE, enhancing its therapeutic potential and reducing the risk of side effects or addiction associated with opioid use.

Discovery

Endogenous morphines first isolated from the brain, enkephalin pentapeptides are associated with nociception by analgesic functions.?There are two types of ENK peptides: methionine ENK (Met-ENK, [Met5]-ENK) and leucine ENK (Leu-ENK, [Leu5]-ENK). The isolation of these peptides from the porcine brain was first reported in 1975.

Structure

The amino acid sequences of Met-ENK (Tyr-Gly-Gly-Phe-Met) and Leu-ENK (Tyr-Gly-Gly-Phe-Leu) are common in mammals. These are generated from the common precursor proenkephalin (PENK or, alternatively, proenkephalin-A [PENK-A]) by proteolytic cleavage.? In addition to Met-ENK and Leu-ENK, several distinct PENK-derived peptides with C-terminal or N-terminal extensions are present in the bovine brain. In mammals, including humans, PENK contains six copies of Met-ENK and one copy of Leu-ENK, whereas in amphibians, lungfish, and sharks, PENK contains seven Met-ENK sequences. In contrast, zebrafish PENK contains five copies of Met-ENK and one copy of Leu-ENK.

Gene, mRNA, and precursor

The human PENK gene, PENK, location 8q23-q24, consists of three exons and has transcription elements such as ENKCRE-1 and ENKCRE-2. The latter acts as an enhancer. A glucocorticoid response element is also present. Human prePENK is composed of 267 aa residues. A signal peptide consisting of 24 aa residues is followed by a cysteine-containing N-terminal sequence and the region containing the repeated ENK sequences.

Receptors

Met-ENK and Leu-ENK are agonists for the δ-opioid receptor (DOR, also known as δ receptor, DOR-1, OP1, etc.) or μ-opioid receptor (MOR; also known as μ receptor, MOR-1, OP3, etc.), both of which are the subtypes of opioid receptors that belong to the GPCR family. Human?DOR is located on chromosome 1 (1p36.1-p34.3). MetENK also interacts with a nonclassical opioid receptor called the opioid growth factor receptor.

Clinical implications

Although MOR agonists are the most commonly used drugs for the treatment of pain, mu agonists show variable efficacy in the treatment of chronic pain, partly because of the development of tolerance. Delta-opioid agonists have been shown to have beneficial effects in chronic pain and emotional disorders, and may potentially be used for treatment in these symptoms.Acute alcohol intoxication stimulates the release of the endogenous opioid peptides β-endorphin, enkephalin, and dynorphin, and nonselective antagonists for opioid receptors reduce alcohol consumption in humans as well as alcohol consumption and self-administration in rats. Selective antagonists of MOR and DOR have been shown to reduce alcohol self-administration. Thus, MOR and DOR are viable targets for reducing the positive reinforcing effects of alcohol in nondependent cohorts.

Biological functions

The effects of morphine represent the functions of endogenous opioid peptides via DOR, KOR, and MOR. In the central nervous system, morphine causes analgesia, euphoria, sedation, miosis (constriction of the pupils), truncal rigidity, nausea, and vomiting, and decreases the rate of respiration and the cough reflex. In the gastrointestinal system, morphine causes constipation, constriction of the biliary smooth muscle, and esophageal reflux, and reduces gastric motility, digestion in the small intestine, and peristaltic waves in the colon. In other smooth muscles, morphine causes urinary retention, depresses renal function, and decreases uterine tone. In the skin, morphine causes itching, sweating, and flushing of the face, neck, and thorax. In the cardiovascular system, morphine decreases blood pressure and the heart rate if the cardiovascular system is stressed. In the immune system, morphine decreases the cytotoxic activity of natural killer cells and the formation of rosettes by human lymphocytes. Morphine also induces behavioral restlessness. Pharmacological studies using both delta agonists and delta antagonists in rodents show that the anxiolytic activity of the opioid tone is mediated by DOR. Although Met-ENK was originally identified as a neuromodulator that interacts with DOR, this peptide was subsequently revealed to be a tonically active regulator of cell proliferation as well.

Synthesis and release

In the rat, glucocorticoid is required for the maintenance of basal Penk mRNA expression in the forebrain, and insulin injection induces an increase in mRNA levels in the adrenal medulla. In humans, as in rats, Met-ENK that is probably derived from the adrenal medulla is present in the circulation. Acupuncture relief of chronic pain syndrome correlates with increased plasma Met-ENK concentration, whereas the level of plasma Met-ENK in chronic alcoholics is reduced.

Biochem/physiol Actions

Antinociceptive activity mediated through the δ1 receptor while the modulatory activity is mediated through the δ2 receptor. Tritiated [D-Pen2,5]-enkephalin is used as a δ1 ligand.

Clinical Use

Nalmefene reduces alcohol consumption in adults with alcohol dependence. Morphine and hydromorphone are used in the treatment and management of severe pain. Naltrexone is used alongside behavioral therapy both for opiate addiction and for alcohol dependency. Naloxone is used to reverse narcotic depression.

InChI:InChI=1/C30H39N5O7S2/c1-29(2)23(34-25(38)20(31)14-18-10-12-19(36)13-11-18)27(40)32-16-22(37)33-21(15-17-8-6-5-7-9-17)26(39)35-24(28(41)42)30(3,4)44-43-29/h5-13,20-21,23-24,36H,14-16,31H2,1-4H3,(H,32,40)(H,33,37)(H,34,38)(H,35,39)(H,41,42)/t20-,21-,23-,24-/m0/s1

Upstream product

• 4530-20-5 BOC-glycine 
• 13734-34-4 N-tert-butoxycarbonyl-L-phenylalanine 
• 3978-80-1 Boc-Tyr-OH 
• 115962-34-0 N^α-Boc-(S-p-MeBzl)-D-penicillamine 
• 100111-01-1 D-pen^2,5-enkephalin 

Relevant academic research and scientific papers

A rapid and facile method for the preparation of peptide disulfides

A selective and efficient method for disulfide bond formation in peptides utilizing carbon tetrachloride in dichloromethane in the presence of tetrabutylammonium fluoride (TBAF) is described. The reaction proceeded rapidly and no side reaction was observed with nucleophilic amino acids such as Met, His, Tyr or Trp. This method has been applied to three model peptides using solution and on-the-resin disulfide formation.

Probing the stereochemical requirements for receptor recognition of δ opioid agonists through topographic modifications in position 1

A series of side-chain constrained tyrosine derivatives, 2',6'-dimethyl-β-methyltyrosines (TMT), has been designed and incorporated into position 1 of the highly selective δ opioid agonists DPDPE (Tyr-D-Pen2-Gly-Phe-D-Pen5-OH) and deltorphin I (DELT I, Tyr-D-Ala-Phe-Asp-Val-Val-Gly-NH2). Molecular mechanics calculations on isolated TMT residues and nuclear magnetic resonance (NMR) studies of the TMT1-containing peptides in DMSO showed that each of the four stereoisomers of TMT favors one particular rotamer of the side-chain χ1 torsional angle. Therefore, substitution of four TMT isomers for Tyr1 allows us to perform a systematic conformational scan through three staggered rotamers of the aromatic side chain, gauche (-), trans, and gauche (+), and to explore specific binding requirements of the receptor in relation to the side chain conformation. The potency and selectivity of four isomers of [TMT1]DPDPE and four isomers of [TMT1]DELT I were evaluated by radioreceptor binding assays in the rat brain using μ- and δ-selective radiolabeled ligands and by bioassays with guinea pig ileum (GPI, μ receptor) and mouse vas deferens (MVD, δ receptor). In the DPDPE series only one isomer, [(2S,3R)-TMT1 ]DPDPE showed high potency and selectivity for the δ opioid receptors. The favorable side-chain rotamers found for this analogue, i.e., the trans rotamer of TMT1 and the gauche (-) rotamer of Phe4, were proposed as the most probable δ receptor-binding conformations of DPDPE analogues. Two [TMT1]DELT I isomers possessed considerable δ receptor potencies. The (2S,3R)-TMT1 isomer appeared to be a superpotent, but moderately δ-selective agonist, while the (2S,3S)-TMT1 isomer showed the highest selectivity for the δ receptors in this series. Surprisingly, [(2R,3R)TMT1]DELT I also was moderately potent at the δ receptor. These results suggest that the δ receptor requirements for the linear DELT I analogues may be satisfied with two different modes of binding of the (2S,3S)- and (2S,3R)TMT1 isomers. This study provides important guidance for the design of peptide and non-peptide ligands selective for the δ opioid receptor.

Topographically designed analogues of [D-Pen,D-Pen5]enkephalin

The conformationally restricted, cyclic disulfide-containing δ opioid receptor selective enkephalin analogue [D-Pen2,D-Pen5]enkephalin (1, DPDPE) was systematically modified topographically by addition of a methyl group at either the