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Name Dr. Laura Hanold
Organization or Institution University of Florida
Presentation Type Poster
Topic Biochemistry / Chem Bio.

Derivatization of macrocyclic tetrapeptide kappa opioid receptor antagonists by hydroxyproline esterification


Laura E. Hanold,a Shainnel O. Eans,b Heather Stacy,b Jay P. McLaughlin,b and Jane V. Aldricha

Author Institution(s)

a) Department of Medicinal Chemistry and b) Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL


Kappa opioid receptor (KOR) antagonists show promise as potential therapeutics to treat substance abuse and mood disorders. Due to this potential, our laboratory has focused on developing peptides as KOR antagonists. The macrocyclic tetrapeptide [D-Trp]CJ-15,208 displays KOR antagonist activity in vivo and blocks stress-induced reinstatement of cocaine-seeking behavior (1). Furthermore, this peptide demonstrates blood-brain barrier permeability after oral administration, a promising characteristic for potential therapeutics to treat substance abuse and mood disorders (2). However, [D-Trp]CJ-15,208 is composed of very hydrophobic residues, which limits its aqueous solubility and can complicate in vivo administration. In order to introduce polar modifications to improve solubility, D-proline was substituted with D-hydroxyproline (D-Hyp), which maintains aromatic side chains and the proline constraint while incorporating a hydroxyl group that acts as a handle for additional modifications. Here, we describe the synthesis of the D-Hyp-containing peptide [D-Hyp2,D-Trp4]CJ-15,208 and its esterification. Preliminary in vivo evaluation indicates that both [D-Hyp2,D-Trp4]CJ-15,208 and its glycine ester derivative maintain KOR antagonist activity following i.c.v. administration in mice in the 55 °C warm water tail withdrawal assay. These results suggest that introduction of polar substituents on the proline ring is tolerated for KOR antagonist activity and is a promising approach to enhancing the aqueous solubility of macrocyclic tetrapeptide KOR antagonists.  Additional studies will be performed to evaluate the solubility, metabolic stability, and blood-brain barrier permeability of the ester derivatives.

1. N.C. Ross, K.J. Reilley, T.F. Murray, J.V. Aldrich, J.P. McLaughlin, British Journal of Pharmacology, 2012, 165, 1097-1108.

2. S.O. Eans, M.L. Ganno, K.J. Reilley, K.A. Patkar, S.N. Senadheera, J.V. Aldrich, J.P. McLaughlin, British Journal of Pharmacology, 2013, 169, 426-436.