The anticonvulsant activities of functionalized N-benzyl 2-acetamidoacetamides. The importance of the 2-acetamido substituent

Choi, David; Stables, James P.; Kohn, Harold

doi:10.1016/s0968-0896(96)00225-8

Cited by 20 publications

(9 citation statements)

References 21 publications

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“…The hydroxy and methoxy groups provided moderate MES activities (ED 50 = >30, <100 mg/kg) but were appreciably less active than the parent FAA. 16 In a similar study, the C(2)-acetamido group of ( R,S )- N ′-benzyl 2-acetamido-3-methoxypropionamide (( R,S )- 26 , ED 50 = 8.3 mg/kg) was replaced with a methyl, hydroxy, and amino group. The methyl and amino groups also resulted in moderate MES activities (ED 50 = >30, <100 mg/kg) but, again, the activities were lower than the corresponding FAA.…”

Section: Resultsmentioning

confidence: 99%

Defining the Structural Parameters That Confer Anticonvulsant Activity by the Site-by-Site Modification of (R)-N′-Benzyl 2-Amino-3-methylbutanamide

et al. 2011

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Primary Amino Acid Derivatives (PAADs) (N′-benzyl 2-substituted 2-amino acetamides) are structurally related to Functionalized Amino Acids (FAAs) (N′-benzyl 2- substituted 2-acetamido acetamides) but differ by the absence of the terminal N-acetyl group. Both classes exhibit potent anticonvulsant activities in the maximal electroshock seizure animal model and the reported structure-activity relationships (SARs) of PAADs and FAAs differ in significant ways. Recently, we documented that PAAD efficacy was associated with a hydrocarbon moiety at the C(2)-carbon, while in the FAAs, a substituted heteroatom one atom removed from the C(2)-center was optimal. Previously in this issue, we showed that PAAD activity was dependent upon the electronic properties of the 4′-N′-benzylamide substituent, while FAA activity was insensitive to electronic changes at this site. In this study, we prepared analogs of (R)-N′-benzyl 2-amino-3-methylbutanamide to identify the structural components for maximal anticonvulsant activity. We demonstrated that the SAR of PAADs and FAAs diverged at the terminal amide site and that PAADs had considerably more structural latitude in the types of units that could be incorporated at this position, suggesting that these compounds function according to different mechanism(s).

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Section: Resultsmentioning

confidence: 99%

Defining the Structural Parameters That Confer Anticonvulsant Activity by the Site-by-Site Modification of (R)-N′-Benzyl 2-Amino-3-methylbutanamide

et al. 2011

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“…Lacosamide ( R -2-acetamido- N -benzyl-3-methoxypropionamide) was purchased from Cayman Chemicals (Ann Arbor, MI) or synthesized as described (Choi et al, 1996) at Purdue University. A 100 mM solution was made up in N-Methylpyrrolidone (MPL) or dimethylsulfoxide (DMSO) and stored in small aliquots at −20°C.…”

Section: Methodsmentioning

confidence: 99%

“…Recently, lacosamide ((R)- N -benzyl 2-acetamido-3-methoxypropionamide (LCM)), a modulator of voltage-gated sodium channels, was approved as a novel anticonvulsant (Choi et al, 1996; Perucca et al, 2008; Curia et al, 2009; Harris and Murphy, 2009; Kelemen and Halasz, 2010). The action of lacosamide is unique in that it retains the ability to selectively enhance slow inactivation of sodium channels without affecting fast inactivation (Errington et al, 2008; Sheets et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Prevention of posttraumatic axon sprouting by blocking collapsin response mediator protein 2-mediated neurite outgrowth and tubulin polymerization

et al. 2012

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Epileptogenesis following traumatic brain injury (TBI) is likely due to a combination of increased excitability, disinhibition, and increased excitatory connectivity via aberrant axon sprouting. Targeting these pathways could be beneficial in the prevention and treatment of posttraumatic epilepsy. Here, we tested this possibility using the novel anticonvulsant (R)-N-benzyl 2-acetamido-3-methoxypropionamide ((R)-lacosamide (LCM) which acts on both voltage-gated sodium channels and collapsin response mediator protein 2 (CRMP2), an axonal growth/guidance protein. LCM inhibited CRMP2-mediated neurite outgrowth, an effect phenocopied by CRMP2 knockdown. Mutation of LCM binding sites in CRMP2 reduced the neurite inhibitory effect of LCM by ~8-fold. LCM also reduced CRMP2-mediated tubulin polymerization. Thus, LCM selectively impairs CRMP2-mediated microtubule polymerization which underlies its neurite outgrowth and branching. To determine whether LCM inhibits axon sprouting in vivo, LCM was injected into rats subjected to partial cortical isolation, an animal model of posttraumatic epileptogenesis that exhibits axon sprouting in cortical pyramidal neurons. Two weeks following injury, excitatory synaptic connectivity of cortical layer V pyramidal neurons was mapped using patch clamp recordings and laser scanning photostimulation of caged glutamate. In comparison to injured control animals, there was a significant decrease in the map size of excitatory synaptic connectivity in LCM-treated rats, suggesting that LCM treatment prevented enhanced excitatory synaptic connectivity due to posttraumatic axon sprouting. These findings suggest, for the first time, that LCM’s mode of action involves interactions with CRMP2 to inhibit posttraumatic axon sprouting.

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“…Lacosamide was first identified as the lead compound in a class of functionalized amino acids demonstrating antiepileptic properties in the maximal electroshock model [2,3]. Lacosamide reduced seizure activity in the genetically susceptible Frings mouse as well as the hippocampal kindled rat [4].…”

Section: Introduction: Lacosamide As a Novel Anti-epilepticmentioning

confidence: 99%

Specific Binding of Lacosamide to Collapsin Response Mediator Protein 2 (CRMP2) and Direct Impairment of its Canonical Function: Implications for the Therapeutic Potential of Lacosamide

Wilson

Khanna

2014

Mol Neurobiol

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The novel anti-epileptic drug lacosamide (LCM; SPM927, Vimpat®) has been heralded as having a dual-mode of action through interactions with both the voltage-gated sodium channel and the neurite outgrowth-promoting collapsin response mediator protein 2 (CRMP2). Lacosamide’s ability to dampen neuronal excitability through the voltage-gated sodium channel likely underlies its efficacy in attenuating the symptoms of epilepsy (i.e. seizures). While the role of CRMP2 in epilepsy has not been well-studied, given the proposed involvement of circuit reorganization in epileptogenesis, the ability of lacosamide to alter CRMP2 function may prove disease-modifying. Recently, however, the validity of lacosamide’s interaction with CRMP2 has come under scrutiny. In this review, we address the contradictory reports concerning the binding of lacosamide to CRMP2, as well as, the ability of lacosamide to directly impact CRMP2 function. Additionally, we address similarly contradicting reports regarding the potential disease-modifying effect of lacosamide on the development and progression of epilepsy. As the vast majority of anti-epileptic drugs influence only the symptoms of epilepsy, the ability to hinder disease progression would be a major breakthrough in efforts to cure or prevent this debilitating syndrome.

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The anticonvulsant activities of functionalized N-benzyl 2-acetamidoacetamides. The importance of the 2-acetamido substituent

Cited by 20 publications

References 21 publications

Defining the Structural Parameters That Confer Anticonvulsant Activity by the Site-by-Site Modification of (R)-N′-Benzyl 2-Amino-3-methylbutanamide

Defining the Structural Parameters That Confer Anticonvulsant Activity by the Site-by-Site Modification of (R)-N′-Benzyl 2-Amino-3-methylbutanamide

Prevention of posttraumatic axon sprouting by blocking collapsin response mediator protein 2-mediated neurite outgrowth and tubulin polymerization

Specific Binding of Lacosamide to Collapsin Response Mediator Protein 2 (CRMP2) and Direct Impairment of its Canonical Function: Implications for the Therapeutic Potential of Lacosamide

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