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Pharmacological characterization of tachykinin tetrabranched derivatives
Author(s) -
Ruzza Chiara,
Rizzi Anna,
Malfacini Davide,
Cerlesi Maria Camilla,
Ferrari Federica,
Marzola Erika,
Ambrosio Caterina,
Gro Cristina,
Severo Salvadori,
Costa Tommaso,
Calo Girolamo,
Guerrini Remo
Publication year - 2014
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.12727
Subject(s) - neurokinin a , neurokinin b , substance p , chemistry , pharmacology , in vivo , receptor , potency , tachykinin receptor , peptide , in vitro , medicine , neuropeptide , biochemistry , biology , microbiology and biotechnology
Background and Purpose Peptide welding technology ( PWT ) is a novel chemical strategy that allows the synthesis of multibranched peptides with high yield, purity and reproducibility. Using this technique, we have synthesized and pharmacologically characterized the tetrabranched derivatives of the tachykinins, substance P ( SP ), neurokinin A ( NKA ) and B ( NKB ). Experimental Approach The following in vitro assays were used: calcium mobilization in cells expressing human recombinant NK receptors, BRET studies of G‐protein – NK 1 receptor interaction, guinea pig ileum and rat urinary bladder bioassays. Nociceptive behavioural response experiments were performed in mice following intrathecal injection of PWT2‐ SP . Key Results In calcium mobilization studies, PWT tachykinin derivatives behaved as full agonists at NK receptors with a selectivity profile similar to that of the natural peptides. NK receptor antagonists display similar potency values when tested against PWT 2 derivatives and natural peptides. In BRET and bioassay experiments PWT 2‐ SP mimicked the effects of SP with similar potency, maximal effects and sensitivity to aprepitant. After intrathecal administration in mice, PWT 2‐ SP mimicked the nociceptive effects of SP , but with higher potency and a longer‐lasting action. Aprepitant counteracted the effects of PWT 2‐ SP in vivo . Conclusions and Implications The present study has shown that the PWT technology can be successfully applied to the peptide sequence of tachykinins to generate tetrabranched derivatives characterized with a pharmacological profile similar to the native peptides. In vivo , PWT 2‐ SP displayed higher potency and a marked prolongation of action, compared with SP .