De novo identification of highly active fluorescent kappa opioid ligands from a rhodamine labeled tetrapeptide positional scanning library Article

Houghten, RA, Dooley, CT, Appel, JR. (2004). De novo identification of highly active fluorescent kappa opioid ligands from a rhodamine labeled tetrapeptide positional scanning library . BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 14(8), 1947-1951. 10.1016/j.bmcl.2004.01.090

cited authors

  • Houghten, RA; Dooley, CT; Appel, JR

authors

abstract

  • Highly active fluorescent compounds having kappa opioid activity were identified following the screening in a kappa-specific radioligand binding assay of a positional scanning tetrapeptide combinatorial library in which every tetrapeptide was fluorescently labeled. Lissamine rhodamine B sulfonyl chloride was coupled to the N terminal of a mixture-based tetrapeptide positional scanning library made up of over 7.3 million tetrapeptides. Upon determination of the most active mixtures for each position of the library in the kappa binding assay, individual rhodamine labeled tetrapeptides were then synthesized and tested to determine their activities. Eight individual rhodamine labeled peptides were identified that were specific for the kappa opioid receptor, having binding affinities ranging from 5-20 nM. These peptides were poor inhibitors at the mu and delta receptors (Ki>5,000 nM). Furthermore, neither rhodamine itself nor these same tetrapeptides lacking the N-terminal rhodamine had any significant activity at the kappa receptor, indicating that both the tetrapeptide sequence and the rhodamine moiety are required for receptor binding. This study has demonstrated that novel fluorescent compounds with intrinsic activity can be identified through the use of combinatorial chemistry. © 2004 Elsevier Ltd. All rights reserved.

publication date

  • April 19, 2004

published in

Digital Object Identifier (DOI)

start page

  • 1947

end page

  • 1951

volume

  • 14

issue

  • 8