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Nerve injury and inflammation cause up-regulation of dynorphin A (Dyn A, H-Tyr-Gly-Gly-PheLeu-Arg-Arg-Ile-Arg-Pro-Lys-Leu-Lys-Trp-Asp-Asn-Gln-OH) in the spinal cord, which results in hyperalgesia via the interaction with bradykinin receptors (BRs) [1]. This is a non-opioid neuroexcitatory effect that cannot be blocked by an opioid antagonist, naloxone. On the basis of the fact, systematic structure-activity relationship study on Dyn A was performed to develop BRs antagonists that can block the hyperalgesia. As a result, LYS1044, [des-Arg]-Dyn A-(4-11), was identified as a lead ligand along with key insights into structural features for the BRs recognition (i.e. amphipathicity) [2-4]. Intrathecal administration of the lead ligand reversed thermal hyperalgesia and mechanical hypersensitivity in nerve injured animals and inhibited non-opioid Dyn A-induced motor impairment and hyperalgesia in naive animals. Yet, this ligand showed very low metabolic stabilities in plasma and was completely degraded within 4 hours of incubation (half-life < 1 hour). Therefore, in an effort to improve the metabolic stability and also to enhance the blood brain barrier permeability, various modifications were performed on Dyn A structure. Here we report design and synthesis of cyclic Dyn A analogues and their biological activities.

Amphipathic Non-opioid Dynorphin A Analogs to Inhibit Neuroexcitatory Effects at Central Bradykinin Receptors