Design, synthesis, and pharmacological activities of dynorphin A analogues cyclized by ring-closing metathesis.
Dynorphin A (Dyn A) is an endogenous ligand for kappa opioid receptors. To restrict the conformational mobility, we synthesized several cyclic Dyn A-(1-11)NH(2) analogues on solid phase utilizing ring-closing metathesis (RCM) between the side chains of allylglycine (AllGly) residues incorporated in positions 2, 5, and/or 8. Cyclizations between the side chains of AllGly gave reasonable yields (56-74%) of all of the desired cyclic peptides. Both the cis and trans isomers were obtained for all of the cyclic peptides, with the ratio of cis to trans isomers depending on the position and stereochemistry of the AllGly. Most of the cyclic Dyn A-(1-11)NH(2) analogues examined exhibit low nanomolar binding affinity for kappa opioid receptors (K(i) = 0.84-11 nM). In two of the three cases, the configuration of the double bond has a significant influence on the opioid receptor affinities and agonist potency. All of the peptides inhibited adenylyl cyclase activity in a concentration-dependent manner with full or close to full agonist activity. These potent Dyn A analogues are the first ones cyclized by RCM.
Fang
Wei-Jie
WJ
Department of Medicinal Chemistry, The University of Kansas, Lawrence, Kansas 66045, USA.
Cui
Yanjun
Y
Murray
Thomas F
TF
Aldrich
Jane V
JV
D000067956:Adenylyl Cyclase Inhibitors; D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D003500:Cyclization; D015195:Drug Design; D004399:Dynorphins / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D008969:Molecular Sequence Data; D051381:Rats; D017473:Receptors, Opioid, kappa / Q000378:metabolism; D013237:Stereoisomerism; D013379:Substrate Specificity
D000067956:Adenylyl Cyclase Inhibitors; D017473:Receptors, Opioid, kappa; D004399:Dynorphins