Design, Synthesis and Pharmacological Characterization of Fluorescein-Derived Endothelin Antagonists Bq-123 And Bq-788

摘要

Endothelin-1 (ET-1) is a 21 amino acid peptide involved in the cardiovascular system. ET-1 binds to two G-protein coupled receptors namely, endothelin receptor A (ET_A) and endothelin receptor B (ET_B). Our goal is to develop fluorescent ET_A and ET_B analogues towards the study of the ET system in situ (in vivo imaging). To date, there is no published data on fluorescent and selective probe for those receptors. We design a strategy to generate FITC-derivative (fluorescein isothiocyanate-derivative) of the known BQ-123 cyclo(Pro-D-Val-Leu-D-Trp-D-Asp) and BQ-788 (N-(cis-2,6-dimethylpiperidinocarbonyl-y-methylleucyl-D-l-(methoxycarbonyl)-tryptophanyl-D-norleucine), two potent and selective antagonists for ET_A and ET_B, respectively. We also provide an in vitro pharmacological profile for each new compound.