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Published on: August 1, 2018
Cyclic analogs of galanin and neuropeptide Y by hydrocarbon stapling
Brad R Green1, Brian D Klein, Hee-Kyoung Lee
1Department of Medicinal Chemistry, College of Pharmacy, University of Utah, Salt Lake City, UT 84108, USA. brad.green@utah.edu
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 (logD). The stapled analogs retained agonist activities towards their respective receptors and suppressed seizures in a mouse model of epilepsy.
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