Design of Analgesic Trivalent Peptides with Low Withdrawal Symptoms: Probing the Antinociceptive Profile of Novel Linear and Cyclic Peptides as Opioid Pan Ligands

Article

作者: Mollica, Adriano ; Tanguturi, Parthasaradhireddy ; Scioli, Giuseppe ; Molnar, Gabriella ; Della Valle, Alice ; Marinaccio, Lorenza ; Streicher, John M. ; Minosi, Paola ; Stefanucci, Azzurra ; Pieretti, Stefano

The discovery of efficacious and safe analgesics with reduced side effects is the foremost challenge in the pain field. In this work, we report the in vitro and in vivo evaluation of linear and cyclic analogues of biphalin with the aim to complete the series of structural modifications previously applied in the development of opioid peptides incorporating a xylene bridge. Replacement of Tyr^1,1' by Dmt (2,5-dimethyltyrosine) in the linear biphalin analogue AM94 and cyclic analogue MACE4 resulted in two new compounds (namely, MJ2 and MJ5) endowed with improved KOR/MOR/DOR binding affinity. Both compounds showed a strong antinociceptive profile in in vivo models of nociception, allodynia, and hyperalgesia via the tail flick, hot plate, and formalin tests after intracerebroventricular and subcutaneous administration. One of these ligands, MJ2, was also tested in tolerance and dependence studies, exhibiting very little withdrawal symptoms.

2013-04-01·Journal of Peptide Science4区 · 生物学

Antinociceptive profile of potent opioid peptide AM94, a fluorinated analogue of biphalin with non‐hydrazine linker

4区 · 生物学

Article

作者: Pieretti, Stefano ; Fidanza, Stefano ; Lucente, Gino ; Costante, Roberto ; Mollica, Adriano ; Pinnen, Francesco ; Stefanucci, Azzurra

AM94 is a fluorinated analog of biphalin with non‐hydrazine linker that has an in vitro affinity for μ‐opioid and δ‐opioid receptors tenfold higher than biphalin. Furthermore, in vivo evaluation in rats showed that AM94 has in hot plate test – after both intracerebroventricular and intravenous administrations – a greater and more durable efficacy than biphalin. Here, the antinociceptive profile of AM94 is further evaluated by following two different administration routes, intrathecal and subcutaneous, and two different animal species, rats and mice. The analgesic potency of AM94 is compared with that of both the parent peptide biphalin and morphine. Results show that in rats (tail flick test) and in mice (formalin test), AM94 has a higher and more durable analgesic effect than biphalin after intrathecal and subcutaneous administrations. Conformational properties of biphalin and AM94 were also investigated by variable‐temperature 1H NMR and energy minimization. Copyright © 2012 European Peptide Society and John Wiley & Sons, Ltd.

2012-06-01·European Journal of Pharmacology3区 · 医学

The analgesic activity of biphalin and its analog AM 94 in rats

3区 · 医学

Article

作者: Giustino Orlando ; Annalisa Chiavaroli ; Adriano Mollica ; Sheila Leone ; Chiara Di Nisio ; Michele Vacca ; Luigi Brunetti

Biphalin is an opioid linear octapeptide, which displays a broad affinity for all opioid receptors (μ, δ and κ), as well as exceptionally high antinociceptive activity. AM 94 is a biphalin analog and a selective agonist at μ and δ opioid receptors. This study investigated the antinociceptive profile of AM 94. All antinociception evaluations were made in adult male rats using the hot-plate test. AM 94 proved to induce greater and longer antinociception compared to biphalin following intracebroventricular (1 nmol/kg) and intravenous administration (1200 nmol/kg) as evaluated by % maximum possible effect (M.P.E.), when administered intracerebroventricularly and intravenously and sustained analgesia up to 210 min. The antinociceptive activities of biphalin and AM 94 were antagonized by naloxone (10mg/kg intraperitoneally). Our data suggest that AM 94 could be regarded as a novel pharmacologically active opioid compound for eliciting potent and sustained analgesia after central and peripheral administration.

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适应症	最高研发状态	国家/地区	公司	日期
轮状病毒感染	临床2期	-	Zenyth Advisors LLC	-
轮状病毒感染	临床2期	-	Murdoch Childrens Research Institute	-
轮状病毒感染	临床2期	澳大利亚	-	-