Preparation and anticonvulsant activity of a series of functionalized .alpha.-heteroatom-substituted amino acids

Kohn, Harold; Kn, Sawhney; P, LeGall; Dw, Robertson; Jd, Leander

doi:10.1021/jm00112a020

Cited by 56 publications

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“…In the sensitive rat (ip) hippocampal kindled seizure test,44,45 its ED 50 value was 12 mg/kg. This closely matched the value for ( R )- 3 (ED 50 = 14 mg/kg) in similar screening 12. The hippocampal kindled seizure assay is a model of partial complex seizures or temporal lobe seizures, which are the most common and drug-resistant type of adult focal epilepsy 45a,46…”

Section: Resultssupporting

confidence: 78%

Merging the Structural Motifs of Functionalized Amino Acids and α-Aminoamides: Compounds with Significant Anticonvulsant Activities

et al. 2010

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Functional amino acids (FAAs) and α-aminoamides (AAAs) are two classes of antiepileptic drugs (AEDs) that exhibit pronounced anticonvulsant activities. We combined key structural pharmacophores present in FAAs and AAAs to generate a new series of compounds and document that select compounds exhibit activity superior to either the prototypical FAA (lacosamide) or the prototypical AAA (safinamide) in the maximal electroshock (MES) seizure model in rats. A representative compound, (R)-N-4′-((3″-fluoro)benzyloxy)benzyl 2-acetamido-3-methoxypropionamide ((R)-10), was tested in the MES (mice, ip), MES (rat, po), psychomotor 6 Hz (32 mA) (mice, ip), and hippocampal kindled (rat, ip) seizure tests providing excellent protection with ED 50 values of 13, 14, ~10 mg/kg, and 12 mg/kg, respectively. In the rat sciatic nerve ligation model (ip), (R)-10 (12 mg/kg) provided an 11.2-fold attenuation of mechanical allodynia. In the mouse biphasic formalin pain model (ip), (R)-10 (15 mg/kg) reduced pain responses in the acute and the chronic inflammatory phases.Epilepsy is a chronic disorder, characterized by recurrent, unprovoked seizures. 1 A seizure is defined as a discrete clinical event arising from transient, hypersynchronous, abnormal neuronal behavior. Epilepsy, then, is not a disease but rather a syndrome arising from a group of nonspecific, dysfunctional events in the brain. The treatment mainstay for patients with epileptic disorders has been the long-term and consistent administration of anticonvulsant drugs. 2,3 There are more than 40 pharmacologic therapies used for the treatment of epilepsy. 4 Unfortunately, even when used optimally, these therapeutic interventions are ineffective for some 30% of patients. 5 Moreover, their use is associated, in more than 40% of patients, with untoward effects (e.g., drowsiness, dizziness, nausea, liver damage). 6 The shortcomings of current regimens highlight the need for new, more effective agents.CORRESPONDING AUTHOR FOOTNOTE: Division of Medicinal Chemistry and Natural Products, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599-7568 and Department of Chemistry, University of North Carolina, Chapel Hill, North Carolina 27599-3290, hkohn@email.unc.edu, Telephone: 919-843-8112, Fax: 919-966-0204. Supporting Information Available: Synthetic procedures for the intermediates leading to the preparation of 5,9, (R)-6-8, (R)-10-22, (S)-6, (S)-10, 74, and 75, elemental analyses, 1 H and 13 C NMR spectra of compounds 5, (R)-6-8, 9, (R)-10-22, (S)-6, (S)-10, 74, and 75 evaluated in this study. This material is available free of charge via the internet at http://pubs.acs.org. NIH Public AccessAuthor Manuscript J Med Chem. Author manuscript; available in PMC 2011 May 13. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptWe have previously reported that functionalized amino acids (FAAs, a 1) [7][8][9][10][11][12][13][14][15][16][17][18] exhibit excellent anticonvulsant activities in various animal seizure models. ...

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Section: Resultssupporting

confidence: 78%

Merging the Structural Motifs of Functionalized Amino Acids and α-Aminoamides: Compounds with Significant Anticonvulsant Activities

et al. 2010

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“…Lacosamide ( R ‐2‐acetamido‐ N ‐benzyl‐3‐methoxypropionamide, SPM 927) previously called harkoseride or ADD234037 is a novel anticonvulsant drug. It belongs to a series of functionalized amino acids which have been synthesized as a new class of anticonvulsant agents (Kohn et al, 1991). Lacosamide has shown activity in a wide variety of animal models for epilepsy including the maximal electroshock test, the rat hippocampal kindling model and different models of self‐sustaining status epilepticus.…”

Section: Introductionmentioning

confidence: 99%

Lacosamide displays potent antinociceptive effects in animal models for inflammatory pain

Stöhr¹,

Krause

Selve

2006

European Journal of Pain

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Lacosamide is a functionalized amino acid which was initially synthesized as an antiepileptic drug. In addition to its broad anti-seizure activity, lacosamide was shown to display efficacy in animal models for neuropathic pain and is currently in phase III clinical development for the treatment of epilepsy and neuropathic pain. In order to further profile its antinociceptive properties, the effects of lacosamide on inflammatory pain in the formalin test, the carrageenan model and the adjuvant-induced arthritis model were investigated. For the formalin test, mice received an intraplantar injection of formalin and the subsequent licking response was measured over 45 min. Lacosamide was administered 30 min before formalin. For the carrageenan model, mechanical and thermal hyperalgesia were assessed 3 h following an intraplantar injection of carrageenan. Lacosamide was administered to rats 30 min before pain threshold measurements. For the adjuvant-induced arthritis test rats received intraplantar injections of Freund's complete adjuvant into the right hindpaw which lead to the development of arthritic symptoms in all animals tested for antinociception. On day 11 after arthritis induction, mechanical hyperalgesia was assessed by the modified Randall Selitto paw pressure test following acute treatment with lacosamide. Lacosamide dose-dependently attenuated mechanical hyperalgesia following carrageenan injection and in rats suffering from Freund's complete adjuvant-induced arthritis. Moreover, thermal hyperalgesia induced by carrageenan as well as the formalin-induced licking response were dose-dependently attenuated by lacosamide. These results suggest lacosamide may be active against various forms of acute and chronic inflammatory pain in humans.

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“…Lacosamide (LCM, Vimpat [Brussels, Belgium], R‐2‐acetamido‐ N ‐benzyl‐3‐methoxypropionamide) is a member of a series of functionalized amino acids that was synthesized as potential anticonvulsant compounds at the University of Houston (Conley & Kohn, ; Kohn et al., , ). Upon testing in the National Institutes of Health (NIH) Anticonvulsant Screening Program it was found to have potential anticonvulsant effects in many animal models of epilepsy including maximal electroshock seizure (MES), the 6‐Hz refractory seizure model, and sound‐induced seizures in Frings mice (Hovinga, ; Stöhr et al., ).…”

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Synergism of lacosamide with established antiepileptic drugs in the 6‐Hz seizure model in mice

et al. 2013

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Summary Purpose Lacosamide (LCM, Vimpat) is an anticonvulsant with a unique mode of action. This provides lacosamide with the potential to act additively or even synergistically with other antiepileptic drugs (AEDs). The objective of this study was to determine the presence of such interactions by isobolographic analysis. Methods The anticonvulsant effect of LCM in combination with other AEDs including carbamazepine (CBZ), phenytoin (PHT), valproate (VPA), lamotrigine (LTG), topiramate (TPM), gabapentin (GBP), and levetiracetam (LEV) at fixed dose ratios of 1:3, 1:1, and 3:1, was evaluated in the 6‐Hz–induced seizure model in mice. In addition, the impact of the combinations of LCM with the other AEDs on motor coordination was assessed in the rotarod test. Finally, AED concentrations were measured in blood and brain to evaluate potential pharmacokinetic drug interactions. Key Findings All studied AEDs produced dose‐dependent anticonvulsant effects against 6‐Hz–induced seizures. Combinations of LCM with CBZ, LTG, TPM, GBP, or LEV were synergistic. All other LCM/AED combinations displayed additive effects with a tendency toward synergism. Furthermore, no enhanced adverse effects were observed in the rotarod test by combining LCM with other AEDs. No pharmacokinetic interactions were seen on brain AED concentrations. Coadministration of LCM and TPM led to an increase in plasma levels of LCM, whereas the plasma concentration of PHT was increased by coadministration of LCM. Significance The synergistic anticonvulsant interaction of LCM with various AEDs, without exacerbation of adverse motor effects, highlights promising properties of LCM as add‐on therapy for drug refractory epilepsy.

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Preparation and anticonvulsant activity of a series of functionalized .alpha.-heteroatom-substituted amino acids

Cited by 56 publications

References 0 publications

Merging the Structural Motifs of Functionalized Amino Acids and α-Aminoamides: Compounds with Significant Anticonvulsant Activities

Merging the Structural Motifs of Functionalized Amino Acids and α-Aminoamides: Compounds with Significant Anticonvulsant Activities

Lacosamide displays potent antinociceptive effects in animal models for inflammatory pain

Synergism of lacosamide with established antiepileptic drugs in the 6‐Hz seizure model in mice

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