Ring size in cyclic endomorphin-2 analogs modulates receptor binding affinity and selectivity

Piekielna, Justyna; Kluczyk, Alicja; Gentilucci, Luca; Cerlesi, Maria Camilla; Calò, Girolamo; Tömböly, Csaba; Łapiński, Krzysztof; Janecki, Tomasz; Janecka, Anna

doi:10.1039/c5ob00565e

Cited by 15 publications

(16 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The reference compound, EM‐2, showed mu affinity in the n M range (Table ), as expected . The cyclic monomer 1 exhibited subnanomolar affinity for mu, similar to that of EM‐2, nanomolar affinity for kappa, and showed also weak binding to delta . The cyclodimer 2 showed comparable affinity for mu and kappa binding sites but with two to three orders of magnitude lower affinity as compared with 1 .…”

Section: Resultssupporting

confidence: 65%

“…This pentapeptide was then cyclized on‐resin through an amide bond between side chains of d‐Lys and Asp residues. As a result, we obtained the expected cyclic monomer 1 and also the cyclic dimer 2 in 70/30 ratio . Cyclic opioid analogs have been extensively tested but in vitro biological properties of the cyclodimeric side‐products were mentioned only in a few articles …”

Section: Introductionmentioning

confidence: 81%

“…Both peaks were separated and characterized by ESI‐MS . The 1 H NMR spectrum of the monomer 1 was published previously, and the 1 H NMR spectrum of the dimer 2 is reported below.…”

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Redoubling the ring size of an endomorphin‐2 analog transforms a centrally acting mu‐opioid receptor agonist into a pure peripheral analgesic

et al. 2016

Self Cite

View full text Add to dashboard Cite

The study reports the synthesis and biological evaluation of two opioid analogs, a monomer and a dimer, obtained as products of the solid-phase, side-chain to side-chain cyclization of the pentapeptide Tyr-d-Lys-Phe-Phe-AspNH2 . The binding affinities to the mu, delta, and kappa opioid receptors, as well as results obtained in a calcium mobilization functional assay are reported. Tyr-[d-Lys-Phe-Phe-Asp]2 -NH2 1 was a potent and selective full agonist of mu with sub-nanomolar affinity, while the dimer (Tyr-[d-Lys-Phe-Phe-Asp]2 -NH2 )2 2 showed a significant mixed mu/kappa affinity, acting as an agonist at the mu. Molecular docking computations were utilized to explain the ability of the dimeric cyclopeptide 2 to interact with the receptor. Interestingly, in spite of the increased ring size, the higher flexibility allowed 2 to fold and fit into the mu receptor binding pocket. Both cyclopeptides were shown to elicit strong antinociceptive activity after intraventricular injection but only cyclomonomer 1 was able to cross the blood-brain barrier. However, the cyclodimer 2 displayed a potent peripheral antinociceptive activity in a mouse model of visceral inflammatory pain. © 2016 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 309-317, 2016.

show abstract

Section: Resultssupporting

confidence: 65%

Section: Introductionmentioning

confidence: 81%

See 1 more Smart Citation

Redoubling the ring size of an endomorphin‐2 analog transforms a centrally acting mu‐opioid receptor agonist into a pure peripheral analgesic

et al. 2016

Self Cite

View full text Add to dashboard Cite

show abstract

“…[17][18][19][20][21][22] As linear peptides often exist in conformational equilibrium, cyclic peptides which adopt better defined conformations were used in many structural studies aimed at understanding the specific requirements of each opioid receptor type. [23][24][25][26] Over the last several years, we have focused our research on the synthesis of cyclic analogues based on the sequence of EM-2, with incorporated bifunctional amino acids that facilitated ring closure. Among the obtained analogues, the cyclic peptide Tyr-c[d-LysÀ PheÀ PheÀ Asp]NH 2 displayed very high affinity at μOR, enzymatic stability and strong and long lasting antinoci-ceptive activity after intra-cerebroventricular (i.c.v.)…”

Section: Introductionmentioning

confidence: 99%

Pharmacological Profile and Molecular Modeling of Cyclic Opioid Analogues Incorporating Various Phenylalanine Derivatives

Adamska‐Bartłomiejczyk

Lipiński

Piekielna-Ciesielska

et al. 2020

ChemMedChem

Self Cite

View full text Add to dashboard Cite

Peptide‐based agonists of the μ opioid receptor (μOR) are promising therapeutic candidates for pain relief with reduced side effects compared to morphine. A deep understanding of μOR–ligand interactions is necessary for future design of peptide‐based opioid analgesics. To explore the requirements of the μOR binding pocket, eight new analogues of our cyclic peptide Tyr‐c[d‐Lys−Phe−Phe−Asp]NH2 displaying high μOR affinity were synthesized, in which Phe in either the third or fourth position was replaced by various derivatives of this amino acid (β3‐Phe, homoPhe, β3‐homoPhe and PhGly). The aim of this research was to examine the structural effects of such modifications on the bioactivity, and both experimental and theoretical methods were used. The binding of the cyclic analogues to all three OR types (μ, δ, κ) was assessed by radioligand competitive binding assay, and their functional activity was determined in a calcium mobilization assay. In order to provide structural hypotheses explaining the obtained experimental affinities, the complexes of the cyclic peptides with μOR were subjected to molecular modeling.

show abstract

“…Cyclic EM-2 analogues were synthesized to investigate the effect of ring size on MOR affinity and selectivity [48]. Tyr-c 2,5 [DLys-Phe-Phe-Asp]-NH 2 , a 17-membered ring, showed high MOR affinity in the picomolar range, but reduced selectivity dramatically (4-fold) by enhancing KOR affinity.…”

Section: Introductionmentioning

confidence: 99%

Cyclic Opioid Peptides

Remesic

Lee

Hruby³

2016

CMC

View full text Add to dashboard Cite

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.

show abstract

Ring size in cyclic endomorphin-2 analogs modulates receptor binding affinity and selectivity

Cited by 15 publications

References 35 publications

Redoubling the ring size of an endomorphin‐2 analog transforms a centrally acting mu‐opioid receptor agonist into a pure peripheral analgesic

Redoubling the ring size of an endomorphin‐2 analog transforms a centrally acting mu‐opioid receptor agonist into a pure peripheral analgesic

Pharmacological Profile and Molecular Modeling of Cyclic Opioid Analogues Incorporating Various Phenylalanine Derivatives

Cyclic Opioid Peptides

Contact Info

Product

Resources

About