Title:Cyclic Opioid Peptides
Volume: 23
Issue: 13
Author(s): Michael Remesic, Yeon Sun Lee and Victor J. Hruby
Affiliation:
Keywords:
Cyclic peptides, polycyclic, opioid receptors, analgesia, central nervous system, blood brain barrier
penetration, bioavailability.
Abstract: For decades the opioid receptors have been an attractive therapeutic target for the
treatment of pain. Since the first discovery of enkephalin, approximately a dozen endogenous
opioid peptides have been known to produce opioid activity and analgesia, but their
therapeutics have been limited mainly due to low blood brain barrier penetration and poor
resistance to proteolytic degradation. One versatile approach to overcome these drawbacks is
the cyclization of linear peptides to cyclic peptides with constrained topographical structure.
Compared to their linear parents, cyclic analogs exhibit better metabolic stability, lower offtarget
toxicity, and improved bioavailability. Extensive structure-activity relationship studies
have uncovered promising compounds for the treatment of pain as well as further elucidate structural elements
required for selective opioid receptor activity. The benefits that come with employing cyclization can
be further enhanced through the generation of polycyclic derivatives. Opioid ligands generally have a short
peptide chain and thus the realm of polycyclic peptides has yet to be explored. In this review, a brief history
of designing ligands for the opioid receptors, including classic linear and cyclic ligands, is discussed along
with recent approaches and successes of cyclic peptide ligands for the receptors. Various scaffolds and approaches
to improve bioavailability are elaborated and concluded with a discourse towards polycyclic peptides.
