Unexpected Opioid Activity Profiles of Analogues of the Novel Peptide Kappa Opioid Receptor Ligand CJ-15,208

被引：32

作者：

Aldrich, Jane V. ^{[1
]}

Kulkarni, Santosh S. ^{[1
]}

Senadheera, Sanjeewa N. ^{[1
]}

Ross, Nicolette C. ^{[2
]}

Reilley, Kate J. ^{[2
]}

Eans, Shainnel O. ^{[2
]}

Ganno, Michelle L. ^{[2
]}

Murray, Thomas F. ^{[3
]}

McLaughlin, Jay P. ^{[2
]}

机构：

[1] Univ Kansas, Dept Med Chem, Lawrence, KS 66045 USA

[2] Torrey Pines Inst Mol Studies, Port St Lucie, FL 34987 USA

[3] Creighton Univ, Sch Med, Omaha, NE 68178 USA

来源：

CHEMMEDCHEM | 2011年 / 6卷 / 09期

关键词：

analgesics; kappa opioid receptor antagonists; peptides; structure-activity relationships; ADMINISTERED ENDOMORPHIN-1; COCAINE-SEEKING; IN-VIVO; ANTAGONIST; MORPHINE; IDENTIFICATION; REINSTATEMENT; A-(1-11)NH2; MODELS; POTENT;

D O I：

10.1002/cmdc.201100113

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

An alanine scan was performed on the novel kappa opioid receptor (KOR) peptide ligand CJ-15,208 to determine which residues contribute to the potent in vivo agonist activity observed for the parent peptide. These cyclic tetrapeptides were synthesized by a combination of solid-phase peptide synthesis of the linear precursors, followed by cyclization in solution. Like the parent peptide, each of the analogues exhibited agonist activity and KOR antagonist activity in an antinociceptive assay in vivo. Unlike the parent peptide, the agonist activity of the potent analogues was mediated predominantly, if not exclusively, by mu opioid receptors (MOR). Thus analogues 2 and 4, in which one of the phenylalanine residues was replaced by alanine, exhibited both potent MOR agonist activity and KOR antagonist activity in vivo. These peptides represent novel lead compounds for the development of peptide-based opioid analgesics.

引用

页码：1739 / 1745

页数：7

共 39 条

[1] Zyklophin, a systemically active selective kappa opioid receptor peptide antagonist with short duration of action [J].