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Modulation of endogenous opioid signaling by inhibitors of puromycin sensitive aminopeptidase.
Singh, Rohit; Jiang, Rongrong; Williams, Jessica; Dobariya, Prakashkumar; Hanak, Filip; Xie, Jiashu; Rothwell, Patrick E; Vince, Robert; More, Swati S.
Afiliación
  • Singh R; Center for Drug Design, College of Pharmacy, University of Minnesota, MN, USA.
  • Jiang R; Center for Drug Design, College of Pharmacy, University of Minnesota, MN, USA.
  • Williams J; Center for Drug Design, College of Pharmacy, University of Minnesota, MN, USA.
  • Dobariya P; Center for Drug Design, College of Pharmacy, University of Minnesota, MN, USA.
  • Hanak F; Department of Neuroscience, University of Minnesota Medical School, Minneapolis, MN, USA.
  • Xie J; Center for Drug Design, College of Pharmacy, University of Minnesota, MN, USA.
  • Rothwell PE; Department of Neuroscience, University of Minnesota Medical School, Minneapolis, MN, USA.
  • Vince R; Center for Drug Design, College of Pharmacy, University of Minnesota, MN, USA.
  • More SS; Center for Drug Design, College of Pharmacy, University of Minnesota, MN, USA.
bioRxiv ; 2024 Apr 03.
Article en En | MEDLINE | ID: mdl-38617237
ABSTRACT
The endogenous opioid system regulates pain through local release of neuropeptides and modulation of their action on opioid receptors. However, the effect of opioid peptides, the enkephalins, is short-lived due to their rapid hydrolysis by enkephalin-degrading enzymes. In turn, an innovative approach to the management of pain would be to increase the local concentration and prolong the stability of enkephalins by preventing their inactivation by neural enkephalinases such as puromycin sensitive aminopeptidase (PSA). Our previous structure-activity relationship studies offered the S-diphenylmethyl cysteinyl derivative of puromycin (20) as a nanomolar inhibitor of PSA. This chemical class, however, suffered from undesirable metabolism to nephrotoxic puromycin aminonucleoside (PAN). To prevent such toxicity, we designed and synthesized 5'-chloro substituted derivatives. The compounds retained the PSA inhibitory potency of the corresponding 5'-hydroxy analogs and had improved selectivity toward PSA. In vivo treatment with the lead compound 19 caused significantly reduced pain response in antinociception assays, alone and in combination with Met-enkephalin. The analgesic effect was reversed by the opioid antagonist naloxone, suggesting the involvement of opioid receptors. Further, PSA inhibition by compound 19 in brain slices caused local increase in endogenous enkephalin levels, corroborating our rationale. Pharmacokinetic assessment of compound 19 showed desirable plasma stability and identified the cysteinyl sulfur as the principal site of metabolic liability. We gained additional insight into inhibitor-PSA interactions by molecular modeling, which underscored the importance of bulky aromatic amino acid in puromycin scaffold. The results of this study strongly support our rationale for the development of PSA inhibitors for effective pain management.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: BioRxiv Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
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XML
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: BioRxiv Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos