No abstract

Background and Purpose Considerable effort has recently been directed at developing multifunctional opioid drugs to minimize the unwanted side effects of opioid analgesics. We have developed a novel multifunctional opioid agonist, DN‐9. Here, we studied the analgesic profiles and related side effects of peripheral DN‐9 in various pain models. Experimental Approach Antinociceptive effects of DN‐9 were assessed in nociceptive, inflammatory, and neuropathic pain. Whole‐cell patch‐clamp and calcium imaging assays were used to evaluate the inhibitory effects of DN‐9 to calcium current and high‐K+‐induced intracellular calcium ([Ca2+]i) on dorsal root ganglion (DRG) neurons respectively. Side effects of DN‐9 were evaluated in antinociceptive tolerance, abuse, gastrointestinal transit, and rotarod tests. Key Results DN‐9, given subcutaneously, dose‐dependently produced antinociception via peripheral opioid receptors in different pain models without sex difference. In addition, DN‐9 exhibited more potent ability than morphine to inhibit calcium current and high‐K+‐induced [Ca2+]i in DRG neurons. Repeated treatment with DN‐9 produced equivalent antinociception for 8 days in multiple pain models, and DN‐9 also maintained potent analgesia in morphine‐tolerant mice. Furthermore, chronic DN‐9 administration had no apparent effect on the microglial activation of spinal cord. After subcutaneous injection, DN‐9 exhibited less abuse potential than morphine, as was gastroparesis and effects on motor coordination. Conclusions and Implications DN‐9 produces potent analgesia with minimal side effects, which strengthen the candidacy of peripherally acting opioids with multifunctional agonistic properties to enter human studies to alleviate the current highly problematic misuse of classic opioids on a large scale.

In a previously described chimeric peptide, we reported that the multifunctional opioid/neuropeptide FF (NPFF) receptor agonist 0 (BN-9) produced antinociception for 1.5 h after supraspinal administration. Herein, four cyclic disulfide analogs containing l- and/or d-type cysteine at positions 2 and 5 were synthesized. The cyclized analogs and their linear counterparts behaved as multifunctional agonists at both opioid and NPFF receptors in vitro and produced potent analgesia without tolerance development. In comparison to 0, cyclized peptide 6 exhibited sevenfold more potent μ-opioid receptor agonistic activity in vitro. Interestingly, the cyclized analog 6 possessed an improved stability in the brain and an increased blood–brain barrier permeability compared to the parent peptide 0 and produced more potent analgesia after supraspinal or subcutaneous administration with improved duration of action of 4 h. In addition, antinociceptive tolerance of analog 6 was greatly reduced after subcutaneous injection compared to fentanyl, as was the rewarding effect, withdrawal reaction, and gastrointestinal inhibition.

Layered transition-metal trichalcogenides have become one of the research frontiers as two-dimensional magnets and candidate materials used for phase-change memory devices. Herein we report the high-pressure synchrotron X-ray diffraction and resistivity measurements on Cr 2 Ge 2 Te 6 (CGT) single crystal by using diamond anvil cell techniques, which reveal a mixture of crystalline-to-crystalline and crystalline-to-amorphous transitions taking place concurrently at 18.3-29.2 GPa. The polymorphic transition could be interpreted by atomic layer reconstruction and the amorphization could be understood in connection with randomly flipping atoms into van der Waals gaps. The amorphous (AM) phase is quenchable to ambient conditions. The electrical resistance of CGT shows a bouncing point at ~ 18 GPa, consistent with the polymorphism phase transition. Interestingly, the highpressure AM phase exhibits metallic resistance with the magnitude comparable to that of high-pressure crystalline phases, whereas the resistance of the AM phase at ambient pressure fails to exceed that of the crystalline phase, indicating that the AM phase of CGT appeared under high pressure is quite unique and similar behavior has never been observed in other phase-change materials. The results definitely would have significant implications for the design of new functional materials.

We previously reported that a multifunctional opioid/neuropeptide FF receptor agonist, DN-9, achieved peripherally restricted analgesia with reduced side effects. To develop stable and orally bioavailable analogues of DN-9, eight lactam-bridged cyclic analogues of DN-9 between positions 2 and 5 were designed, synthesized, and biologically evaluated. In vitro cAMP assays revealed that these analogues, except 7, were multifunctional ligands that activated opioid and neuropeptide FF receptors. Analogue 1 exhibited improved potency for κ-opioid and NPFF 2 receptors. All analogues exhibited potent, long-lasting, and peripherally restricted antinociception in the tail-flick test without tolerance development after subcutaneous administration and produced oral analgesia. Oral administration of the optimized compound analogue 1 exhibited powerful, peripherally restricted antinociceptive effects in mouse models of acute, inflammatory, and neuropathic pain. Remarkably, orally administered analogue 1 had no significant side effects, such as tolerance, dependence, constipation, or respiratory depression, at effective analgesic doses.

No abstract

No abstract

Mounting evidence indicates that the neuropeptide FF (NPFF) system is involved in the side effects of opioid usage, including antinociceptive tolerance, hyperalgesia, abuse, constipation, and respiratory depression. Our group recently discovered that the multitarget opioid/NPFF receptor agonist DN-9 exhibits peripheral antinociceptive activity. To improve its metabolic stability, antinociceptive potency, and duration, in this study, we designed and synthesized a novel cyclic disulfide analogue of DN-9, OFP011, and examined its bioactivity through in vitro cyclic adenosine monophosphate (cAMP) functional assays and in vivo behavioral experiments. OFP011 exhibited multifunctional agonistic effects at the μ-opioid and the NPFF 1 and NPFF 2 receptors and partial agonistic effects at the δand κ-opioid in vitro, as determined via the cAMP functional assays. Pharmacokinetic and pharmacological experiments revealed improvement in its blood− brain barrier permeability after systemic administration. In addition, subcutaneous OFP011 exhibited potent and long-lasting antinociceptive activity via the central μand κ-opioid receptors, as observed in different physiological and pathological pain models. At the highest antinociceptive doses, subcutaneous OFP011 exhibited limited tolerance, gastrointestinal transit, motor coordination, addiction, reward, and respiration depression. Notably, OFP011 exhibited potent oral antinociceptive activities in mouse models of acute, inflammatory, and neuropathic pain. These results suggest that the multifunctional opioid/NPFF receptor agonists with improved blood−brain barrier penetration are a promising strategy for long-term treatment of moderate to severe nociceptive and pathological pain with fewer side effects.