In vitro and in vivo opioid activity of [DPro6]dermorphin, a new dermorphin analogue

Broccardo, Maria; Usenko, A.B.; Uranova, M.G.; Guzevatykh, L. S.; Kamensky, A.A.; Андреева, Л. А.; Alfeeva, L. Yu.; Myasoedov, N. F.; Giannini, Elisa; Improta, Giovanna; Emel'yanova, T. G.

doi:10.1016/s0196-9781(03)00057-3

Cited by 19 publications

(7 citation statements)

References 32 publications

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“…It is well-recognized that the μ opioid system plays a primary role in the inhibitory control of gastrointestinal (GI) motility, one of the most frequent adverse effects of opioid analgesics . Colonic bead expulsion in mice (CBI) was used to assess the effect on GI motility after sc administration. , All tested opioid compounds produced a dose-related inhibition of CBE with ED 50 values ranging between 11.8 and 2491 nmol/kg (Table ).…”

Section: Resultsmentioning

confidence: 99%

Synthesis and Biological Evaluation of 14-Alkoxymorphinans. 22. Influence of the 14-Alkoxy Group and the Substitution in Position 5 in 14-Alkoxymorphinan-6-ones on in Vitro and in Vivo Activities

et al. 2005

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Novel 14-alkoxy-substituted (e.g. allyloxy, benzyloxy, naphthylmethoxy) morphinan-6-one derivatives were synthesized and biologically evaluated. Compounds 6-9 and 11 displayed affinities in the subnanomolar range to mu opioid receptors which were comparable to 14-O-methyloxymorphone (1) and 14-methoxymetopon (3), and higher than oxymorphone (2). Opioid binding affinity was sensitive to the character and length of the substituent in position 14. In smooth muscle preparations they behaved as potent agonists. Antinociceptive potencies of compounds 6-11 in the hot-plate test after sc administration in mice were considerably greater than the potency of morphine. In the colonic propulsion test, the most potent analgesic compound 7 showed negligible constipating activity at the analgesic dose. These findings provide further evidence that the nature of the substituent at position 14 has a major impact on the abilities of morphinans to interact with opioid receptors. Introduction of a 5-methyl group has no significant effect on in vitro biological activities, but resulted in decreased antinociceptive potency.

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Section: Resultsmentioning

confidence: 99%

Synthesis and Biological Evaluation of 14-Alkoxymorphinans. 22. Influence of the 14-Alkoxy Group and the Substitution in Position 5 in 14-Alkoxymorphinan-6-ones on in Vitro and in Vivo Activities

et al. 2005

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“…Gastrointestinal transit was determined using the charcoal meal test according to the procedures described previously . Male Kunming strain mice weighing 20–25 g were fasted individually for 20 h in wire-bottom cages to prevent coprophagy with free access to water before the experiment and then dosed orally with 0.2 mL/mouse of a suspension of a charcoal meal (10% activated charcoal in 5% gum arabic).…”

Section: Methodsmentioning

confidence: 99%

Novel Cyclic Endomorphin Analogues with Multiple Modifications and Oligoarginine Vector Exhibit Potent Antinociception with Reduced Opioid-like Side Effects

Zhang

Wang

et al. 2021

J. Med. Chem.

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Endomorphins (EMs) are potent pharmaceuticals for the treatment of pain. Herein, we investigated several novel EM analogues with multiple modifications and oligoarginine conjugation. Our results showed that analogues 1–6 behaved as potent μ-opioid agonists and enhanced stability and lipophilicity. Analogues 5 and 6 administered centrally and peripherally induced significant and prolonged antinociceptive effects in acute pain. Both analogues also produced long-acting antiallodynic effects against neuropathic and inflammatory pain. Furthermore, they showed a reduced acute antinociceptive tolerance. Analogue 6 decreased the extent of chronic antinociceptive tolerance, and analogue 5 exhibited no tolerance at the supraspinal level. Particularly, they displayed nontolerance-forming antinociception at the peripheral level. In addition, analogues 5 and 6 exhibited reduced or no opioid-like side effects on gastrointestinal transit, conditioned place preference (CPP), and motor impairment. The present investigation established that multiple modifications and oligoarginine-vector conjugation of EMs would be helpful in developing novel analgesics with fewer side effects.

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“…The potency of DER and its analogs have stimulated interest in this group of peptides as a potential new class of analgesics. DER has not been studied in any clinical trials; however, analogs that more easily cross the blood–brain barrier and have longer lasting activity with fewer side effects are being studied (Broccardo et al ., ; Schiller, ; Mizoguchi et al ., ).…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics and pharmacodynamics of dermorphin in the horse

Robinson

Guan

McDonnell

et al. 2014

Vet Pharm & Therapeutics

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Dermorphin is a μ-opioid receptor-binding peptide that causes both central and peripheral effects following intravenous administration to rats, dogs, and humans and has been identified in postrace horse samples. Ten horses were intravenously and/or intramuscularly administered dermorphin (9.3 ± 1.0 μg/kg), and plasma concentration vs. time data were evaluated using compartmental and noncompartmental analyses. Data from intravenous administrations fit a 2-compartment model best with distribution and elimination half-lives (harmonic mean ± pseudo SD) of 0.09 ± 0.02 and 0.76 ± 0.22 h, respectively. Data from intramuscular administrations fit a noncompartmental model best with a terminal elimination half-life of 0.68 ± 0.24 (h). Bioavailability following intramuscular administration was variable (47-100%, n = 3). The percentage of dermorphin excreted in urine was 5.0 (3.7-10.6) %. Excitation accompanied by an increased heart rate followed intravenous administration only and subsided after 5 min. A plot of the mean change in heart rate vs. the plasma concentration of dermorphin fit a hyperbolic equation (simple Emax model), and an EC(50) of 21.1 ± 8.8 ng/mL was calculated. Dermorphin was detected in plasma for 12 h and in urine for 48 or 72 h following intravenous or intramuscular administration, respectively.

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In vitro and in vivo opioid activity of [DPro6]dermorphin, a new dermorphin analogue

Cited by 19 publications

References 32 publications

Synthesis and Biological Evaluation of 14-Alkoxymorphinans. 22. Influence of the 14-Alkoxy Group and the Substitution in Position 5 in 14-Alkoxymorphinan-6-ones on in Vitro and in Vivo Activities

Synthesis and Biological Evaluation of 14-Alkoxymorphinans. 22. Influence of the 14-Alkoxy Group and the Substitution in Position 5 in 14-Alkoxymorphinan-6-ones on in Vitro and in Vivo Activities

Novel Cyclic Endomorphin Analogues with Multiple Modifications and Oligoarginine Vector Exhibit Potent Antinociception with Reduced Opioid-like Side Effects

Pharmacokinetics and pharmacodynamics of dermorphin in the horse

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