[Nalpha-benzylTyr1,cyclo(D-Asp5,Dap8)]- dynorphin A-(1-11)NH2 cyclized in the "address" domain is a novel kappa-opioid receptor antagonist.
The cyclic dynorphin A analogue [N(alpha)-benzylTyr(1),cyclo(D-Asp(5),Dap(8))]dynorphin A-(1-11)NH(2) (Dap = 2,3-diaminopropionic acid) exhibits nanomolar affinity (30 nM) and high selectivity (K(i) ratio (kappa/mu/delta) = 1/194/330) for kappa-opioid receptors. This analogue antagonizes dynorphin A-(1-13)NH(2) at kappa-opioid receptors in the adenylyl cyclase assay (K(B) = 84 nM). This is the first dynorphin A-based antagonist with modifications in the C-terminal "address" domain that alter efficacy and thus represents a novel selective kappa-opioid receptor antagonist.
Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, 21201, USA.
Kshitij A
KA
Patkar
Xiuzhen
X
Yan
Thomas F
TF
Murray
Jane V
JV
Aldrich
D000262:Adenylyl Cyclases / Q000096:biosynthesis; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D003500:Cyclization; D004399:Dynorphins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008968:Molecular Conformation; D010446:Peptide Fragments / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D011869:Radioligand Assay; D017473:Receptors, Opioid, kappa / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D010446:Peptide Fragments; D017473:Receptors, Opioid, kappa; C502814:dynorphin A-(1-11)-NH2, Nalpha-benzylTyr(1)-cyclo(Asp(5)-Dap(8))-; D004399:Dynorphins; D000262:Adenylyl Cyclases