title: Design, synthesis, and pharmacological characterization of novel endomorphin-1 analogues as extremely potent μ-opioid agonists.
abstract: Recently we reported the synthesis and structure-activity study of endomorphin-1 (EM-1) analogues containing novel, unnatural α-methylene-β-aminopropanoic acids (Map). In the present study, we describe new EM-1 analogues containing Dmt(1), (R/S)-βPro(2), and (ph)Map(4)/(2-furyl)Map(4). All of the analogues showed a high affinity for the μ-opioid receptor (MOR) and increased stability in mouse brain homogenates. Of the new compounds, Dmt(1)-(R)-βPro(2)-Trp(3)-(2-furyl)Map(4) (analogue 12) displayed the highest affinity toward MOR, in the picomolar range (Ki(μ) = 3.72 pM). Forskolin-induced cAMP accumulation assays indicated that this analogue displayed an extremely high agonistic potency, in the subpicomolar range (EC50 = 0.0421 pM, Emax = 99.5%). This compound also displayed stronger in vivo antinociceptive activity after iv administration when compared to morphine in the tail-flick test, which indicates that this analogue was able to cross the blood-brain barrier.
authors.affiliation: Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, and Institute of Biochemistry and Molecular Biology, Lanzhou University, Lanzhou 730000, PR China.
authors.forename: Xin
authors.initials: X
authors.lastname: Liu
authors.forename: Yuan
authors.initials: Y
authors.lastname: Wang
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Xing
authors.forename: Jing
authors.initials: J
authors.lastname: Yu
authors.forename: Hong
authors.initials: H
authors.lastname: Ji
authors.forename: Ming
authors.initials: M
authors.lastname: Kai
authors.forename: Zilong
authors.initials: Z
authors.lastname: Wang
authors.forename: Dan
authors.initials: D
authors.lastname: Wang
authors.forename: Yixin
authors.initials: Y
authors.lastname: Zhang
authors.forename: Depeng
authors.initials: D
authors.lastname: Zhao
authors.forename: Rui
authors.initials: R
authors.lastname: Wang
mesh_terms: D000700:Analgesics / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism; D015195:Drug Design; D057809:HEK293 Cells; D006801:Humans; D020935:MAP Kinase Signaling System; D051379:Mice; D008958:Models, Molecular; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D010766:Phosphorylation; D017450:Receptors, Opioid, mu / Q000819:agonists*
chemical_list: D000700:Analgesics; D009842:Oligopeptides; D017450:Receptors, Opioid, mu; C105293:endomorphin 1; D000242:Cyclic AMP