Gram-scale, chemoselective synthesis of N-[2-(5-hydroxy-1H-indol-3-yl)ethyl]-2-oxopiperidine-3-carboxamide (HIOC)

Setterholm, Noah A.; McDonald, Frank E.; Boatright, Jeffrey H; Iuvone, P. Michael

doi:10.1016/j.tetlet.2015.01.167

Cited by 6 publications

(4 citation statements)

References 11 publications

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“…Additionally, LM was compared with the novel full TrkB agonists HIOC (16) and deoxygedunin (DG) (17). HIOC is an N-acetylserotonin (NAS) derivative that exhibits more robust neurotrophic effects than NAS in a TrkB-dependent manner (16,18). DG is a naturally occurring compound in the gedunin family that has shown robust neuroprotective properties in rats in a TrkB-dependent manner (17).…”

Section: Introductionmentioning

confidence: 99%

TrkB agonists prevent postischemic emergence of refractory neonatal seizures in mice

Kipnis¹,

Sullivan²,

Carter³

et al. 2020

JCI Insight

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Section: Introductionmentioning

confidence: 99%

TrkB agonists prevent postischemic emergence of refractory neonatal seizures in mice

Kipnis¹,

Sullivan²,

Carter³

et al. 2020

JCI Insight

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“…Six-membered heterocycles are a key structural motif in a vast number of different physiologically active compounds . The piperidine ring system in particular is one of the most common structural subunits in many drug targets. − HIOC ( 1 ), , ( R )-tiagabine ( 2 ), and pethidine ( 3 ) , are prominent representatives (Figure ). HIOC (1 ) is a lead compound for the development of neuroprotectants used in the therapy of neuro-degenerative diseases, ( R )-tiagabine ( 2 ) is known as a GABA uptake inhibitor and is involved in the treatment of epilepsy, and pethidine ( 3 ) is one of the most widely utilized opioids …”

Section: Introductionmentioning

confidence: 99%

“…HIOC (1) is a lead compound for the development of neuroprotectants 6 used in the therapy of neuro-degenerative diseases, (R)-tiagabine ( 2) is known as a GABA uptake inhibitor 7 and is involved in the treatment of epilepsy, and pethidine (3) is one of the most widely utilized opioids. 8 Likewise, pyrans 10,11 are key constituents in natural products such as (−)-dinemasone B (4), amplexine (5), and semperoside A (6), displaying various biological activities. 12−14 Despite much success, 15 the piperidine and pyran structure motifs remain a demanding challenge for organic synthesis, especially since ex-chiral pool precursors are not broadly available.…”

Section: ■ Introductionmentioning

confidence: 99%

Stereoselective Synthesis of Biologically Relevant Tetrahydropyridines and Dihydro-2H-pyrans via Ring-Expansion of Monocyclopropanated Heterocycles

et al. 2021

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A stereoselective, scalable, and metal-free ringexpansion of monocyclopropanated pyrroles and furans has been developed, leading to value-added highly functionalized tetrahydropyridine and dihydro-2H-pyran derivatives. Featuring a cyclopropylcarbinyl cation rearrangement as the key step, the selective cleavage of the unactivated endocyclic cyclopropane C−C bond is achieved. Targeted transformations of the thus obtained sixmembered heterocycles give access to versatile building blocks with relevance for drug synthesis.

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“…The efficacy of two graded doses (0.25mg/kg [LM] and 2.5mg/kg [LM2.5]) of the BDNF loop II mimetic, LM, was compared to the novel full TrkB agonists HIOC ( 16 ) and DG ( 17 ). HIOC is an N -acetylserotonin (NAS) derivative that exhibits more robust neurotrophic effects than NAS in a TrkB-dependent manner ( 16, 18 ). DG is a naturally occurring compound in the gedunin family that has shown robust neuroprotective properties in rats in a TrkB-dependent manner ( 17 ).…”

Section: Introductionmentioning

confidence: 99%

TrkB agonists prevent post-ischemic BDNF-TrkB mediated emergence of refractory neonatal seizures in CD-1 pups

Kipnis

Sullivan

Carter

et al. 2019

Preprint

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34Refractory neonatal seizures do not respond to first-line anti-seizure medications (ASMs) 35 like phenobarbital (PB), a positive allosteric modulator for GABAA receptors, the most widely 36 used ASM to treat neonatal seizures. GABAA receptor-mediated inhibition is dependent upon 37 neuronal chloride regulation. The electroneutral cation-chloride transporter KCC2 mediates 38 neuronal chloride extrusion; an age-dependent increase of KCC2 expression enables the shift of 39 GABAergic signaling from depolarizing to hyperpolarizing. BDNF-TrkB activation following 40 excitotoxic injury recruits downstream targets like PLCγ1, leading to KCC2 hypofunction. This 41 study investigated the efficacy of partial and full TrkB agonists; LM22A-4 (LM), HIOC and 42 Deoxygedunin (DG) respectively, on PB-refractory seizures, post-ischemic TrkB-pathway 43 activation, and KCC2 membrane stability in a P7 CD-1 mouse model of refractory neonatal 44 seizures. Anti-seizure efficacy was determined by quantifying seizure burdens with continuous 45 video-EEG. LM rescued PB-refractory seizures in a sexually dimorphic manner. LM anti-seizure 46 efficacy was associated with a significant reduction in the post-ischemic phosphorylation of 47 TrkB at Y816, a site known to mediate post-ischemic KCC2 hypofunction via PLCγ1 activation. 48 LM additionally rescued ischemia-induced pKCC2-S940 dephosphorylation preserving its 49 membrane stability. HIOC and DG, two novel full TrkB agonists, also rescued PB-refractoriness 50 and post-ischemic TrkB-PLCγ1 pathway activation. Additionally, chemogenetic inactivation of 51 TrkB significantly reduced post-ischemic neonatal seizure burdens at P7. Developmental 52 expression profiles of TrkB and KCC2 in naïve pups identified developmental differences that 53 may underlie the sex-dependent variance in anti-seizure efficacy. These results support a novel 54 role for the TrkB receptor in the emergence of age-dependent refractory neonatal seizures. 55 56 65 (KCC2) in a mouse model of acute neonatal ischemia associated with phenobarbital (PB)-66 refractory seizures (5). 67The electroneutral cation-chloride transporter KCC2 is the primary neuronal Clextruder 68 and enables hyperpolarizing GABAergic inhibition in the brain. The residue Ser940 (S940) on 69 the C-terminus of KCC2 is associated with its membrane stability and chloride extrusion 70 capacity (6, 7). The developmental switch in GABAergic signaling from depolarizing to 71 hyperpolarizing (8) is enabled by an age-dependent increase of KCC2 expression (9). In the 72 neonatal period, KCC2 expression is low and GABA is depolarizing (8-10). In addition, KCC2 73 is susceptible to degradation following excitotoxic injury (2, 11, 12). In our characterized CD-1 74 mouse model of ischemic neonatal seizures, KCC2 underwent degradation and 75 dephosphorylation of residue S940 (5). This rendered the ASM PB inefficacious (5), as PB is a 76 positive allosteric modulator of GABAA receptors (13). Prevention of BDNF-TrkB mediated 77 KCC2 hypofunction rescued PB-refractori...

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Gram-scale, chemoselective synthesis of N-[2-(5-hydroxy-1H-indol-3-yl)ethyl]-2-oxopiperidine-3-carboxamide (HIOC)

Cited by 6 publications

References 11 publications

TrkB agonists prevent postischemic emergence of refractory neonatal seizures in mice

TrkB agonists prevent postischemic emergence of refractory neonatal seizures in mice

Stereoselective Synthesis of Biologically Relevant Tetrahydropyridines and Dihydro-2H-pyrans via Ring-Expansion of Monocyclopropanated Heterocycles

TrkB agonists prevent post-ischemic BDNF-TrkB mediated emergence of refractory neonatal seizures in CD-1 pups

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