Cyclic Opioid Peptides

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 analogues exhibit better metabolic stability, lower off-target 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 on and concluded with a discourse towards polycyclic peptides.

The Meta-Position of Phe4 in Leu-enkephalin Regulates Potency, Selectivity, Functional Activity, and Signaling Bias at the Delta and Mu Opioid Receptors

“…6 As a neurotransmitter in pain circuits, Leu-enkephalin possesses antinociceptive properties, 7 whereas peripherally, the peptide demonstrates cardiovascular effects 8 and as such, Leu-enkephalin has served as a lead for roughly four decades worth of medicinal chemistry campaigns aimed at developing analogs that interact with excellent potency and selectivity for δ and µORs. 9 These important studies have historically assessed functional activity G protein-coupled signaling pathways, initially by evaluating inhibition of electrically evoked mouse vas deferens contractions, 10 and later through [ 35 S]GTPyS, luminescence and bioluminescence assays. 11 While quantification of G protein activity is well established, techniques to quantitatively measure β-arrestin recruitment have only began to emerge around 2002.…”

“…From a translational perspective, peptide-based probes provide an ideal tool for studying the cardioprotective effects of the δOR, given their low brain penetration. While numerous enkephalin-like peptides have been synthesized that interact with excellent potency and selectivity for δORs and µORs [13], a majority of studies [14] investigating δOR involvement in ischemia have utilized the synthetic peptide D-Ala 2 ,D-Leu 5 -enkephalin (DADLE, Figure 1) [15,16], because DADLE possesses improved proteolytic stability and improved selectivity for δORs over µORs relative to Leu 5 -enkephalin [6,17]. However, DADLE's discovery in 1977 [18], predated identification of β-arrestin as a modulator of opioid signaling [14,[19][20][21], With the use of contemporary cellular assays it is now apparent that DADLE pharmacologically signals similarly to Leu 5 -enkephalin, though it recruits β-arrestin 2 (arrestin 3) slightly more efficaciously.…”

Synthesis of novel norsufentanil analogs via a four‐component Ugi reaction and in vivo, docking, and QSAR studies of their analgesic activity

“…Endogenous opioid peptides are released from neuronal cells and interact with opioid receptors in the nervous system. For example, met‐enkephalin as a pentapeptide is a potent opioid agonist which its effect on the mu‐opioid is weaker than on delta‐opioid receptors (DOR) . Some synthetic exogenous ligands such as sufentanil and its relative compounds are able to interact with opioid receptors as an agonist and activate the receptors.…”

“…For example, met-enkephalin as a pentapeptide is a potent opioid agonist which its effect on the mu-opioid is weaker than on delta-opioid receptors (DOR). [15][16][17] Some synthetic exogenous ligands such as sufentanil and its relative compounds are able to interact with opioid receptors as an agonist and activate the receptors. Combination of mu-opioid agonists with peptides also increase binding affinity of the combined molecules for both mu-and delta-opioid receptors and reduce undesired effects like dependency to opioids.…”

Synthesis and opioid receptor binding of indium (III) and [111In]-labeled macrocyclic conjugates of diprenorphine: novel ligands designed for imaging studies of peripheral opioid receptors

“…11a Accordingly, we are working toward a new generation of hydrophilic radioligands designed for studies of the peripheral opioid receptors. 1,9 Since opioid receptor peptides tend to show limited metabolic stability, 12,13 our focus is on linking small molecules having a potent opioid receptor pharmacophore to a macrocyclic chelator for radiometals. In this regard, we demonstrated that the δ opioid receptor antagonist naltrindole (NTI) can be conjugated to the polyaminocarboxylate DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), such that the derived indium (III) and [ 111 In]-labeled complexes maintain high binding affinity.…”