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NameMr. Grant Simpson
OrganizationUniversity of Florida
TopicOrganic Chemistry

Synthesis and pharmacological evaluation of macrocyclic tetrapeptides as opioid receptor ligands


Grant Simpson1, Micheal Ferracane1,2, Nicolette Ross3, Jay McLaughlin1 and Jane Aldrich1

Author Location(s)

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.