Synthesis and pharmacological evaluation of macrocyclic tetrapeptides as opioid receptor ligands

Grant Simpson¹, Micheal Ferracane^1,2, Nicolette Ross³, Jay McLaughlin¹ and Jane Aldrich¹

1Department of Medicinal Chemistry, University of Florida, Gainesville FL, USA
2Department of Chemistry, University of Redlands, Redlands CA, USA
3Nova Southeastern University, Ft Lauterdale FL, USA

Antagonists of kappa opioid receptors have demonstrated potential to treat addiction and mood disorders including depression. The natural product macrocyclic tetrapeptide CJ-15,208 (cyclo[Phe-D-Pro-Phe-Trp]) has been shown to possess KOR activity (Saito, 2002). Notably, unlike typical peptide-based drugs, CJ-15,208 exhibits activity after oral administration and can cross the blood-brain barrier to antagonize a centrally administered KOR agonist (Aldrich, 2013). We are synthesizing analogues of the lead compound to explore its structure-activity relationships and to improve its pharmacokinetic properties. Fmoc solid phase synthesis was employed to synthesize the linear precursors, followed by cyclization in solution using an optimized procedure. Following purification, the peptides are evaluated in vivo in an antinociceptive assay (the mouse 55 ^oC warm-water tail-withdrawal assay) for both opioid agonist and antagonist activity. Preliminary results indicated that substitutions could be made in the lead peptide with retention of its mixed agonist/KOR antagonist profile. The synthesis and pharmacological evaluation of selected analogues will be presented. Research supported by grant R01 DA023924 from NIDA.