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Results: 4

1.
Figure 1

Figure 1. From: DEVELOPMENT AND IN VITRO CHARACTERIZATION OF A NOVEL BIFUNCTIONAL MU-AGONIST/DELTA-ANTAGONIST OPIOID TETRAPEPTIDE.

Structures of parent peptides (A) JOM-6 and (B) JOM-13 and new analogs (C) KSK-102 and (D) KSK-103.

Lauren C. Purington, et al. ACS Chem Biol. ;6(12):1375-1381.
2.
Figure 2

Figure 2. From: DEVELOPMENT AND IN VITRO CHARACTERIZATION OF A NOVEL BIFUNCTIONAL MU-AGONIST/DELTA-ANTAGONIST OPIOID TETRAPEPTIDE.

Computational modeling of KSK-103 in MOR and DOR ligand binding pockets reveals structural determinants of ligand efficacy. KSK-103 can be docked without steric hindrances into the ligand binding pocket of the MOR models in the active (A) and inactive (B) conformations, but displays significant overlap between Aci3 of the ligand and Met199 of the receptor in the DOR active conformation (C). This overlap is removed in the DOR inactive conformation, where Met199 is shifted away from the ligand binding pocket (D)

Lauren C. Purington, et al. ACS Chem Biol. ;6(12):1375-1381.
3.
Figure 3

Figure 3. From: DEVELOPMENT AND IN VITRO CHARACTERIZATION OF A NOVEL BIFUNCTIONAL MU-AGONIST/DELTA-ANTAGONIST OPIOID TETRAPEPTIDE.

KSK-103 behaves as a MOR agonist and DOR antagonist in the [35S]GTPγS stimulation assay. Incorporation of [35S]GTPγS as a measure of G protein stimulation was analyzed in cell membrane preparations from C6-rat glioma cells stably expressing either MOR or DOR. (A) At MOR, KSK-103 behaved as a partial agonist, producing 59 ± 11% stimulation of G protein compared to MOR agonist DAMGO (filled squares). Morphine (open circles) and endomorphin-2 (filled triangles) produced a similar percent stimulation; however, they were less potent than KSK-103. (B) Addition of 100 nM KSK-103 (open circles) produced a 26–fold rightward shift in the concentration-response curve for DPDPE at DOR, affording a Ke value for the antagonist of 4.4 ± 1.4 nM.

Lauren C. Purington, et al. ACS Chem Biol. ;6(12):1375-1381.
4.
Figure 4

Figure 4. From: DEVELOPMENT AND IN VITRO CHARACTERIZATION OF A NOVEL BIFUNCTIONAL MU-AGONIST/DELTA-ANTAGONIST OPIOID TETRAPEPTIDE.

KSK-103 is a DOR antagonist in adenylyl cyclase inhibition while reference peptides DIPP(Ψ)NH2 and UFP-505 display partial agonist efficacies. Inhibition of forskolin-stimulated cAMP production was measured utilizing a whole cell assay in C6-rat glioma cells stably expressing DOR. (A) In this assay, 10 μM KSK-103 (filled circle) was unable to significantly inhibit forskolin-stimulated cAMP levels (91 ± 6%) while addition of 100 nM KSK-103 (open triangles) produced a 9.5-fold rightward shift in the concentration-response curve for DPDPE. This afforded a Ke value for antagonism of 12 ± 3.3 nM. (B) Peptides DIPP(Ψ)NH2 (filled squares) and UFP-505 (open triangles) behaved as partial agonists at DOR in this assay, able to reduce forskolin-stimulated cyclase to 65 ± 10% and 72 ± 2%, of controls respectively. 1 μM DOR peptide agonist DPDPE (filled diamond) inhibited forskolin stimulation to 52 ± 12%.

Lauren C. Purington, et al. ACS Chem Biol. ;6(12):1375-1381.

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