Abstract:Sequential modification of the previously identified 4-[3-aryl-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ols led to the identification of a new series of 1-(2-morpholin-2-ylethyl)-3-aryl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxides that are potent and selective inhibitors of the norepinephrine transporter over both the serotonin and dopamine transporters. One representative compound 10b (WYE-114152) had low nanomolar hNET potency (IC(50) = 15 nM) and good selectivity for hNET over h… Show more
“…The successful story of dezocine in controlling perioperative pain is helpful to validate an effective therapeutic approach. Spinal norepinephrine plays an important role in pain transmission and transduction, including potentiation of μ-opioid activity 37 , and NRIs have been used for decades in treatment of chronic pain 38 39 . Because of the synergistic analgesic effect, even relatively moderate activity in the two target sites (μM in NRI for dezocine) within a given chemical molecule may be sufficient to produce strong analgesia.…”
Section: Discussionmentioning
confidence: 99%
“…Although etiologies are different, neuropathic pain is all related to nerve injury and principally involves the N -methyl- D -aspartate receptor-dependent central sensitization, disruption of descending inhibition, and glia activation 48 . The unique noradrenergic input and its combination with the opioid mechanism have a particular advantage in treatment of neuropathic pain 37 38 39 41 43 and NRIs have been used in treatment of chronic pain. Indeed, a single subcutaneous dezocine produced pronounced mechanical antiallodynia and thermal antihyperalgesia in neuropathy, with duration slightly longer and potency slightly higher than morphine.…”
Dezocine is the number one opioid painkiller prescribed and sold in China, occupying 44% of the nation’s opioid analgesics market today and far ahead of the gold-standard morphine. We discovered the mechanisms underlying dezocine antihypersensitivity activity and assessed their implications to antihypersensitivity tolerance. Dezocine, given subcutaneously in spinal nerve-ligated neuropathic rats, time- and dose-dependently produced mechanical antiallodynia and thermal antihyperalgesia, significantly increased ipsilateral spinal norepinephrine and serotonin levels, and induced less antiallodynic tolerance than morphine. Its mechanical antiallodynia was partially (40% or 60%) and completely (100%) attenuated by spinal μ-opioid receptor (MOR) antagonism or norepinephrine depletion/α2-adrenoceptor antagonism and combined antagonism of MORs and α2-adenoceptors, respectively. In contrast, antagonism of spinal κ-opioid receptors (KORs) and δ-opioid receptors (DORs) or depletion of spinal serotonin did not significantly alter dezocine antiallodynia. In addition, dezocine-delayed antiallodynic tolerance was accelerated by spinal norepinephrine depletion/α2-adenoceptor antagonism. Thus dezocine produces antihypersensitivity activity through spinal MOR activation and norepinephrine reuptake inhibition (NRI), but apparently not through spinal KOR and DOR activation, serotonin reuptake inhibition or other mechanisms. Our findings reclassify dezocine as the first analgesic of the recently proposed MOR-NRI, and reveal its potential as an alternative to as well as concurrent use with morphine in treating pain.
“…The successful story of dezocine in controlling perioperative pain is helpful to validate an effective therapeutic approach. Spinal norepinephrine plays an important role in pain transmission and transduction, including potentiation of μ-opioid activity 37 , and NRIs have been used for decades in treatment of chronic pain 38 39 . Because of the synergistic analgesic effect, even relatively moderate activity in the two target sites (μM in NRI for dezocine) within a given chemical molecule may be sufficient to produce strong analgesia.…”
Section: Discussionmentioning
confidence: 99%
“…Although etiologies are different, neuropathic pain is all related to nerve injury and principally involves the N -methyl- D -aspartate receptor-dependent central sensitization, disruption of descending inhibition, and glia activation 48 . The unique noradrenergic input and its combination with the opioid mechanism have a particular advantage in treatment of neuropathic pain 37 38 39 41 43 and NRIs have been used in treatment of chronic pain. Indeed, a single subcutaneous dezocine produced pronounced mechanical antiallodynia and thermal antihyperalgesia in neuropathy, with duration slightly longer and potency slightly higher than morphine.…”
Dezocine is the number one opioid painkiller prescribed and sold in China, occupying 44% of the nation’s opioid analgesics market today and far ahead of the gold-standard morphine. We discovered the mechanisms underlying dezocine antihypersensitivity activity and assessed their implications to antihypersensitivity tolerance. Dezocine, given subcutaneously in spinal nerve-ligated neuropathic rats, time- and dose-dependently produced mechanical antiallodynia and thermal antihyperalgesia, significantly increased ipsilateral spinal norepinephrine and serotonin levels, and induced less antiallodynic tolerance than morphine. Its mechanical antiallodynia was partially (40% or 60%) and completely (100%) attenuated by spinal μ-opioid receptor (MOR) antagonism or norepinephrine depletion/α2-adrenoceptor antagonism and combined antagonism of MORs and α2-adenoceptors, respectively. In contrast, antagonism of spinal κ-opioid receptors (KORs) and δ-opioid receptors (DORs) or depletion of spinal serotonin did not significantly alter dezocine antiallodynia. In addition, dezocine-delayed antiallodynic tolerance was accelerated by spinal norepinephrine depletion/α2-adenoceptor antagonism. Thus dezocine produces antihypersensitivity activity through spinal MOR activation and norepinephrine reuptake inhibition (NRI), but apparently not through spinal KOR and DOR activation, serotonin reuptake inhibition or other mechanisms. Our findings reclassify dezocine as the first analgesic of the recently proposed MOR-NRI, and reveal its potential as an alternative to as well as concurrent use with morphine in treating pain.
“…Briefly, synthesis of (2S)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-1-(methylamino)butan-2-ol followed the route described by Neill et al [20, 21]. For more details, see Additional file 1.…”
Section: Methodsmentioning
confidence: 99%
“…1). In general, the designed benzothidiazole dioxides exhibits excellent affinity and selectivity as well as slightly reduced flexibility compared to other previously published benzoimidazolones [20, 21]. Hence, these substances offer an ideal basis for the further development of novel NET ligands for PET imaging.Fig.…”
BackgroundThe norepinephrine transporter (NET) has been demonstrated to be relevant to a multitude of neurological, psychiatric and cardiovascular pathologies. Due to the wide range of possible applications for PET imaging of the NET together with the limitations of currently available radioligands, novel PET tracers for imaging of the cerebral NET with improved pharmacological and pharmacodynamic properties are needed.MethodsThe present study addresses the radiosynthesis and first preclinical evaluation of the novel NET PET tracer [11C]Me@HAPTHI by describing its affinity, selectivity, metabolic stability, plasma free fraction, blood–brain barrier (BBB) penetration and binding behaviour in in vitro autoradiography.Results[11C]Me@HAPTHI was prepared and displayed outstanding affinity and selectivity as well as excellent in vitro metabolic stability, and it is likely to penetrate the BBB. Moreover, selective NET binding in in vitro autoradiography was observed in human brain and rat heart tissue samples.ConclusionsAll preclinical results and radiosynthetic key-parameters indicate that the novel benzothiadiazole dioxide-based PET tracer [11C]Me@HAPTHI is a feasible and improved NET radioligand and might prospectively facilitate clinical NET imaging.Electronic supplementary materialThe online version of this article (doi:10.1186/s13550-015-0113-3) contains supplementary material, which is available to authorized users.
“…Therefore, the temperature gradient is an important parameter tuning neurotransmitter release and reuptake as it controls the vesicular transmitter content and the amount of the transmitter released with the process of vesicle fusion. The temperature variation during the release and reuptake of NE is oxidative phosphorylation (OXPHOS)-dependent; thus, it is closely coupled to the metabolic state of the NE concentration, especially in the clinical treatment of neurological disorders by the NE reuptake inhibitors reboxetine and atomoxetine. − …”
A long-standing challenge has been the simultaneous sensing of intracellular temperature and norepinephrine (NE) variations to explore signaling pathways and depression pathogeny. Here, we designed a fluorescent probe using poly(N-isopropylacrylamide) and 1- [4-(7-nitrobenzo [1,2,5]for simultaneously measuring the temperature and NE with high selectivity. The fluorescence intensity of the PNIPAm−AANBD moiety exhibited a good response to temperature changes. The PHE moiety could selectively sense NE due to the naphthalic anhydride group in PHE, which formed naphthalimide upon bonding with the primary amino group of NE. The hydroxyl-terminated ligand recognized the phenolic hydroxyl group of NE through the formation of hydrogen bonds. Using the proposed fluorescent probe, variations in the intracellular temperature and NE during NE reuptake could be simultaneously measured. It was first discovered that with the inhibition of antidepressant drugs, the intracellular temperature increased by 1.2−2.1 °C, and the NE reuptake decreased by about 21.5 μM. The measured variations in intracellular temperature and NE during neurotransmitter reuptake can shed light on the underlying mechanism of neurotransmitter signaling pathways, which may facilitate the treatment of depression.
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