Cyclic analogs of galanin and neuropeptide Y by hydrocarbon stapling.

Abstract Hydrocarbon stapling is an effective strategy to stabilize the helical conformation of bioactive peptides. Here we describe application of stapling to anticonvulsant neuropeptides, galanin (GAL) and neuropeptide Y (NPY), that are implicated in modulating seizures in the brain. Dicarba bridges were rationally introduced into minimized analogs of GAL and NPY resulting in increased α-helical content, in vitro metabolic stability and n -octanol/water partitioning coefficient (log  D ). The stapled analogs retained agonist activities towards their respective receptors and suppressed seizures in a mouse model of epilepsy.