Physicochemical and pharmacokinetic properties of novel macro-cyclic peptide kappa opioid receptor ligands
Khaliq1, A. Joshi1, S. Senadheera1, A. Mukhopadhyay1, S. M. Lunte2, J. V. Aldrich1
Dept. of Medicinal Chemistry1 and Dept. of Pharmaceutical Chemistry2 The University of Kansas, Lawrence, KS, USA
We are interested in metabolically stable peptidic ligands for kappa opioid receptors (KOR) as potential treatments for drug abuse and pain. The natural product CJ 15,208, a macrocyclic tetrapeptide (cyclo[L-Phe-D-Pro-L-Phe-Trp]), was reported to exhibit KOR antagonism in vitro (Saito et al., J. Antibiot. 2002, 55, 847). The L-Trp (CJ-15,208) and its D-Trp isomer exhibited different pharmacological profile in vivo after intracerebroventricular administration to mice (Ross et al., Br. J. Pharmacol. 2012, 165, 1097), and both exhibit oral activity. Hence both can serve as lead compounds for further exploration. In order to enhance the oral activity of these macrocyclic peptides and guide the exploration of their analogs, we have examined the physicochemical and pharmacokinetic properties of these two lead compounds. Because of their hydrophobicity we have examined various solubilizing agents, including organic cosolvents, cyclodextrins and surfactants that are compatible with in vitro and in vivo studies, to solubilize these compounds. We have studied the bidirectional permeability of these compounds in the Caco-2 cell monolayer model for intestinal absorption using liquid chromatography-tandem mass spectrometry (LC-MS/MS) to quantify the compounds. The interaction of the compounds with recombinant P-glycoprotein was also evaluated directly using an enzymatic assay. In addition the stability of the compounds in blood and liver homogenate was determined by measuring their disappearance over an incubation time by LC-MS/MS. The results of these studies will be presented. It is imperative to evaluate the physicochemical and pharmacokinetic properties of these lead compounds in their development for in vivo studies and as potential therapeutic agents.
Research supported by NIDA grant R01 DA023924.