Biochemical Pharmacology p. 1887 - 1895 (2004)
Update date:2022-08-03
Topics:
Pil, Joost
Van Der Veken, Pieter
Bal, Gunther
Augustyns, Koen
Haemers, Achiel
Tytgat, Jan
A challenge in opioid peptide chemistry and pharmacology is the possibility to develop novel peptides with peripheral selectivity. An enzymatically stable opioid peptide could involve an antidiarrheal effect. For this reason, we constrained the highly selective and potent tetrapeptide morphiceptin with a 6-atom bridge, resulting in a cyclic amide and an ester analogue, 2 and 3, respectively. Taking advantage of the functional coupling of the opioid receptor with the heteromultimeric G-protein-coupled inwardly rectifying K+ (GIRK1/GIRK2) channel, either the wild-type μ-, κ-, δ- or a mutated μ-opioid receptor (hMORS329A) was functionally co-expressed with GIRK1/GIRK2 channels and a regulator of G-protein signaling (RGS4) in Xenopus laevis oocytes. The two-microelectrode voltage clamp technique was used to measure the opioid receptor activated GIRK1/GIRK2 channel responses. Both cyclic analogues were equally potent via the wild-type μ-opioid receptor hMORwt (EC50 value 976.5±41.7 for 2 and 1017.7±60.7 for 3), while the EC50 value for Tyr-Pro-Phe-D-Pro-NH2 measured 59.3±4.8 nM. These three agonists displayed a four to five times decreased potency via hMORS329A as compared to the wild type. Interestingly, no effect on κ- and δ-opioid receptors was observed. The intramolecular bridge created by cyclization of morphiceptin prevents dipeptidyl peptidase IV from interacting with these analogues. We conclude that constraining morphiceptin with a 6-atom bridge resulted in enzymatically stable peptidomimetics that are exclusively active on μ-opioid receptors. These analogues provide an interesting template in the promising approach for the design of potential antidiarrheal agents.
View MoreChangzhou LanXu Chemical Co.,ltd.
Contact:86-0519-86330911,13656129734,15261186386
Address:Room 524, Depart.Chemical, Changzhou Science and Eductaion town, Jiangsu, China;Factory: Haian Fine Chemical Industry Park,Nantong,Jiangsu,China
Puyang Huicheng Electronic Material Co., Ltd
website:http://huichengchem.weba.testwebsite.cn/index_en.html
Contact:+86-393-8910800
Address:West Section Shengli Road, Puyang457000, China
Contact:86-512-87182056
Address:No.128 Fangzhou Rd, Suzhou Industrial Park, China, 215125, China
website:http://www.sagechem.com
Contact:+86-571-86818502
Address:Room C1301, New Youth Plaza, 8 Jia Shan Road, Hangzhou, China
Contact:86-27-84888681
Address:Wuhan economic & technology development zone
Doi:10.1021/ja01463a040
(1961)Doi:10.1021/ol9000137
(2009)Doi:10.1021/acs.oprd.8b00043
(2018)Doi:10.1271/bbb.100646
(2010)Doi:10.1021/ol802942j
(2009)Doi:10.1023/A:1022592302936
(2002)