Discovery of Amphipathic Dynorphin A Analogues to Inhibit the Neuroexcitatory Effects of Dynorphin A through Bradykinin Receptors in the Spinal Cord
作者： Yeon Sun Lee , Dhanasekaran Muthu , Sara M. Hall , Cyf Ramos-Colon , David Rankin
DOI: 10.1021/JA501677Q
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摘要: We hypothesized that under chronic pain conditions, up-regulated dynorphin A (Dyn A) interacts with bradykinin receptors (BRs) in the spinal cord to promote hyperalgesia through an excitatory effect, which is opposite well-known inhibitory effect of opioid receptors. Considering structural dissimilarity between Dyn and endogenous BR ligands, (BK) kallidin (KD), this interaction could not be predicted, but it allowed us discover a potential neuroexcitatory target. Well-known BK, [des-Arg10, Leu9]-kallidin (DALKD), HOE140 showed different binding profiles at rat brain BRs than previously reported. These results suggest neuronal central nervous system (CNS) may pharmacologically distinct from those defined non-neuronal tissues. Systematic structure–activity relationship (SAR) study was performed, as result, new key feature for recognition identified: amphipathicity....
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