Abstract:
:In a previously described chimeric peptide, we reported that the multifunctional opioid/neuropeptide FF (NPFF) receptor agonist 0 (BN-9) produced antinociception for 1.5 h after supraspinal administration. Herein, four cyclic disulfide analogs containing l- and/or d-type cysteine at positions 2 and 5 were synthesized. The cyclized analogs and their linear counterparts behaved as multifunctional agonists at both opioid and NPFF receptors in vitro and produced potent analgesia without tolerance development. In comparison to 0, cyclized peptide 6 exhibited sevenfold more potent μ-opioid receptor agonistic activity in vitro. Interestingly, the cyclized analog 6 possessed an improved stability in the brain and an increased blood-brain barrier permeability compared to the parent peptide 0 and produced more potent analgesia after supraspinal or subcutaneous administration with improved duration of action of 4 h. In addition, antinociceptive tolerance of analog 6 was greatly reduced after subcutaneous injection compared to fentanyl, as was the rewarding effect, withdrawal reaction, and gastrointestinal inhibition.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Zhang M,Xu B,Li N,Liu H,Shi X,Zhang Q,Shi Y,Xu K,Xiao J,Chen D,Zhu H,Sun Y,Zhang T,Zhang R,Fang Qdoi
10.1021/acs.jmedchem.0c01367subject
Has Abstractpub_date
2020-12-24 00:00:00pages
15709-15725issue
24eissn
0022-2623issn
1520-4804journal_volume
63pub_type
杂志文章abstract::Recruitment of suppressive CD4+ FOXP3+ regulatory T cells (Treg) to the tumor microenvironment (TME) has the potential to weaken the antitumor response in patients receiving treatment with immuno-oncology (IO) agents. Human Treg express CCR4 and can be recruited to the TME through the CC chemokine ligands CCL17 and CC...
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