High impact information on E-2078

• However, SC E-2078 caused diuresis, and this effect was blocked by quadazocine pretreatment, consistent with mediation by kappa-opioid receptors [1].
• OBJECTIVE: The main objective of this study was to compare the effects of s.c. E-2078, a stable dynorphin A(1-8) analog, with two synthetic kappa-opioid ligands, spiradoline (a reference arylacetamide kappa-agonist) and ICI204,448 (a "peripherally selective" kappa-agonist) in behavioral and neuroendocrine endpoints in rhesus monkeys [2].
• RESULTS: E-2078 and ICI204,448 (0.1-3.2 mg/kg) caused increases in sedation and muscle relaxation scores, but were less potent and apparently less effective than spiradoline (0.001-0.1 mg/kg) up to the highest doses presently studied [2].
• Dynorphin A (1-8) analog, E-2078, crosses the blood-brain barrier in rhesus monkeys [3].
• Dynorphin A (1-8) analog, E-2078, is stable in human and rhesus monkey blood [4].

Biological context of E-2078

• In addition, E-2078 caused a long lasting decrease in blood pressure which was blocked completely by pretreatment of the animal with 1 mg/kg of naltrexone [5].
• Absorptive-mediated endocytosis of a dynorphin-like analgesic peptide, E-2078 into the blood-brain barrier [6].
• The i.v. administration of E-2078 ([N-methyl-Tyr1-N-methyl-Arg7-D-Leu8]-dynorphin-A-(1-8) ethylamide) to conscious animals in doses of 15, 50 or 200 micrograms/rat caused a dose-related diuretic response associated with a significant in crease in glomerular filtration rate (GFR) and in blood pressure [5].
• Minor biotransformation products from E-2078, such as E (1-4), E (1-5) and E (3-6), were detected in vitro in some human and rhesus monkey blood, but they made up less than 5% of the total starting E-2078 peptide [4].
• The bioavailabilities of E-2078 after rectal administration, subcutaneous injection, intramuscular injection, and oral administration were 21.6, 67.8, 67.1, 0.7%, respectively [7].

Anatomical context of E-2078

• These results demonstrate that E-2078 is internalized by brain capillaries via absorptive-mediated endocytosis, which is a polycation-sensitive pathway [6].
• Mass spectrometric analysis of the cerebrospinal fluid samples collected after E-2078 injection detected the presence of E-2078, indicating that E-2078 had crossed the blood-brain barrier [3].
• Place aversions were also observed after microinjections of U50,488H and E-2078 into the nucleus accumbens, medial prefrontal cortex and lateral hypothalamus [8].
• E-2078, a potent, selective and stable dynorphin analog with preferential activity for the kappa-opioid receptor subtype on the mouse vas deferens neuroeffector junction [9].
• In microscopic studies, E-2078 caused little or no damage to the rectal mucosa in rats [7].

Associations of E-2078 with other chemical compounds

• The profile of opioid activity of E-2078, a synthetic stable dynorphin analog, was examined in the mouse vas deferens bioassay and compared to that of methionine enkephalin and nonpeptide kappa agonists in the absence and in the presence of selective antagonists for the mu-, kappa- and delta-opioid receptor subtypes [9].

Analytical, diagnostic and therapeutic context of E-2078

• Spinal kappa receptor-mediated analgesia of E-2078, a systemically active dynorphin analog, in mice [10].
• E-2078 is a very stable dynorphin analog that has the same affinity and selectivity for opioid receptors as dynorphin-A by in vitro bioassay [11].
• When E-2078 was administered subcutaneously and naloxone or nor-binaltorphine were given either intracerebroventricularly or intrathecally, the analgesic action of E-2078 was most potently and totally reversed by intrathecal injection of nor-binaltorphimine [10].
• Consonant with the studies in conscious rats, perfusion of isolated rat kidneys with 0.2 to 1.8 microM E-2078 increased urine flow in a dose-dependent manner, and this effect was prevented by the simultaneous perfusion of 2 microM naltrexone with the peptide [5].
• In vivo transport of a dynorphin-like analgesic peptide, E-2078, through the blood-brain barrier: an application of brain microdialysis [12].

References