Discovery of Stable Non-opioid Dynorphin A Analogues Interacting at the Bradykinin Receptors for the Treatment of Neuropathic Pain.
Dynorphin A (Dyn A) is a unique endogenous ligand that possesses well-known neuroinhibitory effects via opioid receptors with a preference for the kappa receptor but also neuroexcitatory effects, which cause hyperalgesia. We have shown that the neuroexcitatory effects are mediated through bradykinin (BK) receptors and that intrathecal (i.th.) administration of our lead ligand 1, [des-Arg7]-Dyn A-(4-11), which shows good binding affinity (IC50= 150 nM) at the BK receptors, blocks Dyn A-induced hyperalgesia in naïve animals and reverses thermal and tactile hypersensitivities in a dose-dependent manner in nerve-injured animals. However, 1 has a serious drawback as a potential drug candidate for the treatment of neuropathic pain because of its susceptibility to enzymatic degradation. In an effort to increase its stability, we modified ligand 1 using non-natural amino acids and found that analogues substituted at or near the N-terminus with a d-isomer retain binding at the receptor and provide a large increase in stability. In particular when Leu5was modified, with either the d-isomer or N-methylation, there was a large increase in stability (t1/2= 0.7-160 h in rat plasma) observed. From these studies, we have developed a very stable Dyn A analogue 16, [d-Leu5,des-Arg7]-Dyn A-(4-11), that binds to BK receptors (IC50= 130 nM) in the same range as ligand 1 and shows good antihyperalgesic effects in both naïve rats and L5/L6spinal nerve ligation rats.
Department of Chemistry and Biochemistry, University of Arizona , Tucson, Arizona 85721, United States.
Sara M
SM
Hall
Department of Chemistry and Biochemistry, University of Arizona , Tucson, Arizona 85721, United States.
Lindsay
L
LeBaron
Department of Chemistry and Biochemistry, University of Arizona , Tucson, Arizona 85721, United States.
Cyf
C
Ramos-Colon
Department of Pharmacology, University of Arizona , Tucson, Arizona 85719, United States.
Chaoling
C
Qu
Department of Pharmacology, University of Arizona , Tucson, Arizona 85719, United States.
Jennifer Yanhua
JY
Xie
Department of Pharmacology, University of Arizona , Tucson, Arizona 85719, United States.
Frank
F
Porreca
Department of Pharmacology, University of Arizona , Tucson, Arizona 85719, United States.
Josephine
J
Lai
Department of Chemistry and Biochemistry, University of Arizona , Tucson, Arizona 85721, United States.
Yeon Sun
YS
Lee
Department of Chemistry and Biochemistry, University of Arizona , Tucson, Arizona 85721, United States.
Victor J
VJ
Hruby
D018712:Analgesics, Non-Narcotic / Q000097:blood / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D055808:Drug Discovery; D004355:Drug Stability; D004399:Dynorphins / Q000737:chemistry; D006801:Humans; D008297:Male; D009437:Neuralgia / Q000188:drug therapy* / Q000378:metabolism*; D011485:Protein Binding; D017207:Rats, Sprague-Dawley; D018002:Receptors, Bradykinin / Q000378:metabolism*
D018712:Analgesics, Non-Narcotic; D018002:Receptors, Bradykinin; D004399:Dynorphins
Antihyperalgesic effect; Bradykinin receptors; Neuropathic pain; Non-opioid dynorphin A; Peptide stability; Structure−activity relationship