Cryogenic Matrix Photochemistry

Bucher, Götz

doi:10.1201/b12252-13

Cited by 3 publications

(3 citation statements)

References 64 publications

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“…Electrophilic (isothiocyanate ( R )- 5 ) and photolabile (azide ( R )- 6 , (trifluoromethyl)diazirine ( R )- 7 ) AB groups were evaluated. Both AB types have been used in target modification studies − . We included the ( R )- 1 AB&CR agent, ( R )- 8 , in which the AB group was an isothiocyanate and the CR group was an alkyne unit.…”

Section: Resultsmentioning

confidence: 99%

Development and Characterization of Novel Derivatives of the Antiepileptic Drug Lacosamide That Exhibit Far Greater Enhancement in Slow Inactivation of Voltage-Gated Sodium Channels

Wang¹,

Park²,

Salomé³

et al. 2010

ACS Chem. Neurosci.

106

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The novel antiepileptic drug, (R)-N-benzyl 2-acetamido-3-methoxypropionamide ((R)-lacosamide, Vimpat® ((R)-1)), was recently approved in the US and Europe for adjuvant treatment of partial-onset seizures in adults. (R)-1 preferentially enhances slow inactivation of voltage-gated Na+ currents, a pharmacological process relevant in the hyperexcitable neuron. We have advanced a strategy to identify lacosamide binding partners by attaching affinity bait (AB) and chemical reporter (CR) groups to (R)-1 to aid receptor detection and isolation. We showed that select lacosamide AB and AB&CR derivatives exhibited excellent activities similar to (R)-1 in the maximal electroshock seizure model in rodents. Here, we examined the effect of these lacosamide AB and AB&CR derivatives and compared them with (R)-1 on Na+ channel function in CNS catecholaminergic (CAD) cells. Using whole-cell patch clamp electrophysiology, we demonstrated that the test compounds do not affect the Na+ channel fast inactivation process, that they were far better modulators of slow inactivation than (R)-1, and that modulation of the slow inactivation process was stereospecific. The lacosamide AB agents that contained either an electrophilic isothiocyanate ((R)-5) or a photolabile azide ((R)-8) unit upon AB activation gave modest levels of permanent Na+ channel slow inactivation, providing initial evidence that these compounds may have covalently reacted with their cognate receptor(s). Our findings support the further use of these agents to delineate the (R)-1–mediated Na+ channel slow inactivation process.

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Section: Resultsmentioning

confidence: 99%

Development and Characterization of Novel Derivatives of the Antiepileptic Drug Lacosamide That Exhibit Far Greater Enhancement in Slow Inactivation of Voltage-Gated Sodium Channels

Wang¹,

Park²,

Salomé³

et al. 2010

ACS Chem. Neurosci.

106

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“…While the intramolecular C–H insertion of transient nitrenes is a well-known reaction, − efficient intermolecular C–H insertion reactions are limited to highly electrophilic nitrenes. Examples are fluorinated phenyl (R = C 6 H n F 5– n )-, − cyano (R = NC)-, carbonyl (R = R′CO)-, , and oxycarbonylnitrenes (R = R′OCON), − as well as the “inorganic” sulfonyl (R = R′S(O) 2 )- , and phosphorylnitrenes (R = (R′O) 2 P(O)). , Furthermore, transition-metal-mediated amination or amidation of C–H bonds is currently receiving significant attention. − …”

Section: Introductionmentioning

confidence: 99%

C–H Bond Amination by Photochemically Generated Transient Borylnitrenes at Room Temperature: A Combined Experimental and Theoretical Investigation of the Insertion Mechanism and Influence of Substituents

Filthaus

Schwertmann²,

Neuhaus³

et al. 2012

Organometallics

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A number of azidoboranes having substitution patterns that are derived from catechol (3), pinacol (4a), 1,2-diaminoethane (4b,c), 1,2-ethanedithiol (4d), and 1,2,4,5-tetrahydroxybenzene as well as acyclic dialkoxy species (5) were synthesized and, in the case of 4c (N,N′-ditosyl-2-azido-1,3,2-diazaborolane), also structurally characterized. The azidoboranes were photolyzed in cyclohexane solvent in order to investigate the tendency of the generated borylnitrenes to undergo intermolecular C−H insertion reactions. The yields of intermolecular insertion products ranged from very good (4a) to vanishingly small, depending on the substitution of the azidoborane. For a number of borylnitrenes the zero-field splitting parameter D was measured in organic glasses at 4 K. The small primary kinetic isotope effect (k H /k D = 1.35) measured for 4a in mixtures of [H 12 ]cyclohexane and [D 12 ]cyclohexane suggests that the insertion reaction is concerted and involves the singlet state of the borylnitrene. Computations at the CBS-QB3 and CCSD(T)/TZ2P levels of theory show that the relative energies of singlet and triplet states of a wide variety of borylnitrenes and even their nature as minima or saddle points depend strongly on the substituents. Photolysis of the most reactive azidoborane, 4a, in methane in a flow reactor at atmospheric pressure produces an intermolecular insertion product in low yields, in agreement with the expectation of intersystem crossing to the less reactive triplet state of the borylnitrene.

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“…Affinity baits are chemical reactive units that lead to irreversible, covalent modification of the receptor when they are appended to a ligand (drug) (Figure , 2 + 3 ⇌ 4 → 5 ). − This technology has been used to identify binding partners and their approximate binding location when ligand binding is modest. Different electrophilic and photoactivable affinity bait units have been advanced. − Among the electrophilic affinity baits are isothiocyanate and acrylamide groups. − ,− Isothiocyanates and acrylamides display an excellent balance between stability and reactivity; they do not readily react with hydroxylic solvents (thus permitting their dissolution in aqueous solutions) but do react with biological nucleophiles (e.g., thiols, amines) with minimal nonspecific background labeling of cellular constituents. ,− …”

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confidence: 99%

Discovery of Lacosamide Affinity Bait Agents That Exhibit Potent Voltage-Gated Sodium Channel Blocking Properties

Park

Yang

Lee

et al. 2013

ACS Chem. Neurosci.

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Lacosamide ((R)-1) is a recently marketed, first-in-class, antiepileptic drug. Patch-clamp electrophysiology studies are consistent with the notion that (R)-1 modulates voltage-gated Na(+) channel function by increasing and stabilizing the slow inactivation state without affecting fast inactivation. The molecular pathway(s) that regulate slow inactivation are poorly understood. Affinity baits are chemical reactive units, which when appended to a ligand (drug) can lead to irreversible, covalent modification of the receptor thus permitting drug binding site identification including, possibly, the site of ligand function. We describe, herein, the synthesis of four (R)-1 affinity baits, (R)-N-(4″-isothiocyanatobiphenyl-4'-yl)methyl 2-acetamido-3-methoxypropionamide ((R)-8), (S)-N-(4″-isothiocyanatobiphenyl-4'-yl)methyl 2-acetamido-3-methoxypropionamide ((S)-8), (R)-N-(3″-isothiocyanatobiphenyl-4'-yl)methyl 2-acetamido-3-methoxypropionamide ((R)-9), and (R)-N-(3″-acrylamidobiphenyl-4'-yl)methyl 2-acetamido-3-methoxypropionamide ((R)-10). The affinity bait compounds were designed to interact with the receptor(s) responsible for (R)-1-mediated slow inactivation. We show that (R)-8 and (R)-9 are potent inhibitors of Na(+) channel function and function by a pathway similar to that observed for (R)-1. We further demonstrate that (R)-8 function is stereospecific. The calculated IC50 values determined for Na(+) channel slow inactivation for (R)-1, (R)-8, and (R)-9 were 85.1, 0.1, and 0.2 μM, respectively. Incubating (R)-9 with the neuronal-like CAD cells led to appreciable levels of Na(+) channel slow inactivation after cellular wash, and the level of slow inactivation only modestly decreased with further incubation and washing. Collectively, these findings have identified a promising structural template to investigate the voltage-gated Na(+) channel slow inactivation process.

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Cryogenic Matrix Photochemistry

Cited by 3 publications

References 64 publications

Development and Characterization of Novel Derivatives of the Antiepileptic Drug Lacosamide That Exhibit Far Greater Enhancement in Slow Inactivation of Voltage-Gated Sodium Channels

Development and Characterization of Novel Derivatives of the Antiepileptic Drug Lacosamide That Exhibit Far Greater Enhancement in Slow Inactivation of Voltage-Gated Sodium Channels

C–H Bond Amination by Photochemically Generated Transient Borylnitrenes at Room Temperature: A Combined Experimental and Theoretical Investigation of the Insertion Mechanism and Influence of Substituents

Discovery of Lacosamide Affinity Bait Agents That Exhibit Potent Voltage-Gated Sodium Channel Blocking Properties

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