Cyclic side-chain-linked opioid analogs utilizing cis - and trans -4-aminocyclohexyl- d -alanine

Piekielna, Justyna; Gentilucci, Luca; Marco, Rossella De; Perlikowska, Renata; Adamska, Anna; Olczak, Jacek; Mazur, Marzena; Artali, Roberto; Modranka, Jakub; Janecki, Tomasz; Tömböly, Csaba; Janecka, Anna

doi:10.1016/j.bmc.2014.10.022

Cited by 12 publications

(10 citation statements)

References 26 publications

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“…Subsequently, the plausible binding modes of 2 within the mu opioid receptor were discussed with the aid of Molecular Docking computations. Previous Docking analysis showed that the cyclopeptide 1 was able to interact effectively with the binding site of the mu receptor, providing a complex perfectly inserted in the binding pocket of the receptor . The expected ionic interaction between the quaternary nitrogen and the receptor residue Asp 147 (or 3:32 in the Ballesteros–Weinstein numbering system), belonging to TM3, was found (Figure ).…”

Section: Resultsmentioning

confidence: 90%

“…The opioid receptor binding assays were performed according to the modified method described by Misicka et al, adopted in our laboratory, using brain homogenates of adult male Wistar rats (for mu‐ and delta‐opioid receptors) or adult male Dunkin Hartley guinea pigs (for kappa‐opioid receptor). The opioid receptor binding affinities for mu, delta, and kappa were determined by radioligand competition analysis using [ 3 H]DAMGO, [ 3 H][Ile ,6 ]deltorphin‐2, and [ 3 H]nor‐BNI, respectively, as specific radioligands.…”

Section: Methodsmentioning

confidence: 99%

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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

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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.

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Section: Resultsmentioning

confidence: 90%

Section: Methodsmentioning

confidence: 99%

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

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“…3, 1 in solution). 29 On the other hand, molecular docking analy- 29 performed on our model of the human MOP receptor, obtained by homology modelling 30 subsequently validated using the crystallographic structure disclosed in 2012, 31 showed that this peptide adopted a different conformation at the MOP receptor. The conformations obtained from the initial "blind docking" were optimized by combined quantum mechanics/molecular mechanics computations using a flexible receptor environment.…”

Section: Correlation Between Ring Size and Receptor Affinity/selectivitymentioning

confidence: 82%

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

et al. 2015

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The study reports the solid-phase synthesis and biological evaluation of a series of new side chain-toside chain cyclized opioid peptide analogs of the general structure Tyr-[D-Xaa-Phe-Phe-Asp]NH 2 , where Xaa = Lys (1), Orn (2), Dab (3), or Dap (4) (Dab = 2,4-diaminobutyric acid, Dap = 2,3-diaminopropionic acid), containing 17-to 14-membered rings. The influence of the ring size on binding to the MOP, DOP and KOP opioid receptors was studied. In general, the reduction of the size of the macrocyclic ring

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“…The most potent analogues contained the Phe(4-F) or Phe(2,4-difluoro) moiety and showed full MOR agonist with slight KOR agonist activity and a strong antinociceptive effect by intracerebroventricular or intraperitoneal injection, indicating high potential of BBB penetration. To further constrain the analogues, DLys was substituted with cis- or trans-4-aminocyclohexyl-D-alanine (D-ACAla) to use as a bridge moiety [52]. This series of analogues gave decent affinities for the MOR and interestingly those with the trans-D-ACAla showed high affinity for the DOR unlike the cis-isomer and other analogues.…”

Section: Introductionmentioning

confidence: 99%

Cyclic Opioid Peptides

Remesic

Lee

Hruby³

2016

CMC

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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.

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Cyclic side-chain-linked opioid analogs utilizing cis - and trans -4-aminocyclohexyl- d -alanine

Cited by 12 publications

References 26 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

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

Cyclic Opioid Peptides

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