Identification of Stabilized Dynorphin Derivatives for Suppressing Tolerance in Morphine-Dependent Rats

Al-Fayoumi, Suliman; Brúgós, Boglárka; Arya, Vikram; Mulder, Esther; Eppler, Bärbel; Mauderli, André P.; Hochhaus, Günther

doi:10.1023/b:pham.0000036920.50291.5b

Cited by 7 publications

(7 citation statements)

References 26 publications

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“…Dyn A-(1-13) analogs that have been stabilized to metabolism at the N-and C-termini by incorporation of either an N-MeTyr and/or C-terminal amide, respectively, have also been evaluated in vivo (117,118). These analogs enhanced morphine analgesia in morphine-tolerant rats following both intravenous and pulmonary delivery, with effects observed for up to 3.4 and 4.4 h, respectively, after administration of [N-MeTyr 1 ]Dyn A-(1-13) amide by these two routes.…”

Section: Dynorphin a Analogs And Other Kor Peptides Studied In Vivomentioning

confidence: 99%

Peptide Kappa Opioid Receptor Ligands: Potential for Drug Development

Aldrich

McLaughlin

2009

AAPS J

114

102

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While narcotic analgesics such as morphine, which act preferentially through mu opioid receptors, remain the gold standard in the treatment of severe pain, their use is limited by detrimental liabilities such as respiratory depression and drug dependence. Thus, there has been considerable interest in developing ligands for kappa opioid receptors (KOR) as potential analgesics and for the treatment of a variety of other disorders. These include effects mediated both by central receptors, such as antidepressant activity and a reduction in cocaine-seeking behavior, and activity resulting from the activation of peripheral receptors, such as analgesic and anti-inflammatory effects. While the vast majority of opioid receptor ligands that have progressed in preclinical development have been small molecules, significant advances have been made in recent years in identifying opioid peptide analogs that exhibit promising in vivo activity. This review will focus on possible therapeutic applications of ligands for KOR and specifically on the potential development of peptide ligands for these receptors.

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Section: Dynorphin a Analogs And Other Kor Peptides Studied In Vivomentioning

confidence: 99%

Peptide Kappa Opioid Receptor Ligands: Potential for Drug Development

Aldrich

McLaughlin

2009

AAPS J

114

102

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“…In a previous study, 17 the metabolic stability of N-and C-terminal modifications of Dyn A (1-13) derivatives in human plasma was investigated and it was reported that one of the derivatives, N-MT Dyn A amide, showed a half-life in human plasma that was more than 100 times longer than that of Dyn A(1-13). The same study revealed on a qualitative level that these modifications remained pharmacologically active.…”

Section: Discussionmentioning

confidence: 99%

“…17 Among the peptides tested, [N-Met-Tyr 1 ]-Dynorphine A(1-13) amide (N-MT Dyn A amide) proved to be the most stable derivative, with a halflife of more than 2 hours (130 minutes) in vitro. 17 Previous studies using Dyn A (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13) showed that the activity of dynorphins was affected by their route of administration. Activity was observed after intravenous and intrathecal administration, but not intracerebroventricular or subcutaneous administration in morphine-dependent mice and rats.…”

Section: Introductionmentioning

confidence: 99%

“…Dynorphin A(1-13) (Dyn A(1-13)), a metabolic fragment of Dyn A (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17), was first isolated by Goldstein from porcine pituitary. 1 In vivo studies have shown that Dyn A(1-13) itself does not have a significant analgesic effect, [2][3][4] however the peptide facilitates analgesia in morphine-tolerant mice.…”

Section: Introductionmentioning

confidence: 99%

“…[13][14][15][16] We evaluated N-and C-terminal modifications of dynorphin A (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13). 17 Among the peptides tested, [N-Met-Tyr 1 ]-Dynorphine A(1-13) amide (N-MT Dyn A amide) proved to be the most stable derivative, with a halflife of more than 2 hours (130 minutes) in vitro. 17 Previous studies using Dyn A (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13) showed that the activity of dynorphins was affected by their route of administration.…”

Section: Introductionmentioning

confidence: 99%

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Stabilized dynorphin derivatives for modulating antinociceptive activity in morphine tolerant rats: Effect of different routes of administration

Brúgós

Arya

Hochhaus

2004

AAPS J

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Dynorphins, such as dynorphin A(1-13) (Dyn A(1-13)), have been shown to enhance analgesia in morphine-tolerant animals, despite their very short half-life after intravenous administration. The potential use of dynorphins in humans is therefore of interest. This laboratory has recently evaluated the metabolic fate of stabilized dynorphin derivatives. This study was conducted to evaluate whether such stabilized derivatives, ie, [NMet-Tyr 1 ]-Dynorphin A(1-13) (N-MT Dyn A, stabilized at the N-terminal end) and [N-Met-Tyr 1 ]-Dynorphin A(1-13) amide (N-MT Dyn A amide, stabilized at the C-and N-terminal ends), would enhance the antinociceptive activity of morphine not only after intravenous administration but also after subcutaneous and pulmonary delivery. Intravenous administration of N-MT Dyn A (5 µmol/kg) and N-MT Dyn A amide (5 µmol/kg) to morphine-tolerant rats resulted in significantly higher tail-flick latencies than those observed for the saline group. These effects could be observed for up to 2.0 ± 0.1 hours after intravenous administration of N-MT Dyn A and for up to 3.4 ± 1.4 hours for N-MT Dyn A amide. The time-averaged effects of both peptides were similar. After pulmonary delivery of the same dose, derivatives remained active. The duration of the effects after pulmonary administration of the amide was 4.4 ± 2.5 hours while that of N-MT Dyn A was slightly shorter (2.8 ± 0.9 hours). No effect was observed after subcutaneous administration of N-MT Dyn A. These results suggest that pulmonary delivery of stabilized dynorphin derivatives represents a possible alternative to intravenous administration.

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