Marked stereospecificity in a new class of anticonvulsants

Kohn, Harold; Conley, Judith D.; Leander, J. David

doi:10.1016/0006-8993(88)90709-3

Cited by 41 publications

(63 citation statements)

References 11 publications

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“…Accordingly, ( R )-enantiomer of lacosamide exhibited potent anticonvulsant effect, whereas ( S )-enantiomer was virtually inactive in MES model. Likewise, additional studies have clearly shown that anticonvulsant effect of several functionalized amino acids and derivatives thereof resided in the ( R )-enantiomers whereas ( S )-enantiomers were almost inactive 56,58,59. Notably, our major findings for in vivo anti-convulsant activity of the novel ligands 1 – 6 investigated in MES model correlated directly with their observed in vitro hH 3 R antagonist affinity.…”

Section: Discussionsupporting

confidence: 70%

Anticonvulsant effects of isomeric nonimidazole histamine H<sub>3</sub> receptor antagonists

Sadek

Saad

Schwed

et al. 2016

DDDT

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Phenytoin (PHT), valproic acid, and modern antiepileptic drugs (AEDs), eg, remacemide, loreclezole, and safinamide, are only effective within a maximum of 70%–80% of epileptic patients, and in many cases the clinical use of AEDs is restricted by their side effects. Therefore, a continuous need remains to discover innovative chemical entities for the development of active and safer AEDs. Ligands targeting central histamine H3 receptors (H3Rs) for epilepsy might be a promising therapeutic approach. To determine the potential of H3Rs ligands as new AEDs, we recently reported that no anticonvulsant effects were observed for the (S)-2-(4-(3-(piperidin-1-yl)propoxy)benzylamino)propanamide (1). In continuation of our research, we asked whether anticonvulsant differences in activities will be observed for its R-enantiomer, namely, (R)-2-(4-(3-(piperidin-1-yl)propoxy)benzylamino)propaneamide (2) and analogs thereof, in maximum electroshock (MES)-, pentylenetetrazole (PTZ)-, and strychnine (STR)-induced convulsion models in rats having PHT and valproic acid (VPA) as reference AEDs. Unlike the S-enantiomer (1), the results show that animals pretreated intraperitoneally (ip) with the R-enantiomer 2 (10 mg/kg) were moderately protected in MES and STR induced models, whereas proconvulsant effect was observed for the same ligand in PTZ-induced convulsion models. However, animals pretreated with intraperitoneal doses of 5, 10, or 15 mg/kg of structurally bulkier (R)-enantiomer (3), in which 3-piperidinopropan-1-ol in ligand 2 was replaced by (4-(3-(piperidin-1-yl)propoxy)phenyl)methanol, and its (S)-enantiomer (4) significantly and in a dose-dependent manner reduced convulsions or exhibited full protection in MES and PTZ convulsions model, respectively. Interestingly, the protective effects observed for the (R)-enantiomer (3) in MES model were significantly greater than those of the standard H3R inverse agonist/antagonist pitolisant, comparable with those observed for PHT, and reversed when rats were pretreated with the selective H3R agonist R-(α)-methyl-histamine. Comparisons of the observed antagonistic in vitro affinities among the ligands 1–6 revealed profound stereoselectivity at human H3Rs with varying preferences for this receptor subtype. Moreover, the in vivo anticonvulsant effects observed in this study for ligands 1–6 showed stereoselectivity in different convulsion models in male adult rats.

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Section: Discussionsupporting

confidence: 70%

Anticonvulsant effects of isomeric nonimidazole histamine H<sub>3</sub> receptor antagonists

Sadek

Saad

Schwed

et al. 2016

DDDT

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“…We showed that 1 compounds containing a small R substituent provided excellent seizure protection in the MES test and that anticonvulsant activity typically improved when a substituted heteroatom was introduced one atom removed from the C(2) center. Moreover, anticonvulsant activity for the 1 compounds principally resided in the D-configuration 9,10,11,16,18. Thus, we progressively increased the R substituent in 5–8 from hydrogen to methyl to isopropyl to tert -butyl and then included in our selection list 9 and 10 , compounds that contained a substituted heteroatom positioned one atom removed from C(2).…”

Section: Resultsmentioning

confidence: 99%

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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“…Peptidomimetics with some of these modified side chains have been synthesized and incorporated in the design of numerous drug candidates (30)(31)(32)(33)(34)(35)(36)(37). Contour thickness decreases as its value relative to the global minimum increases.…”

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confidence: 99%

Conformational studies on model dipeptides of Gly, L ‐Ala and their C^α‐substituted analogs

Ramnarayan¹,

Chan²,

Balaji³

et al. 1995

International Journal of Peptide and Protein Research

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As a part of the development of conformational guidelines for the design of metabolically altered peptidomimetics, we present conformational energy calculations on model dipeptide compounds with glycine (Gly), L-alanine (Ala), r-aminoisobutyric acid (Aib), L-terr-butylglycine (Tle), L-phenylglycine (Phg), (.,a)diphenylglycine (Dqg), L-2-aminobutyric acid (Abu), 2-amino-2-ethylbutync acid (Deg), ~-2-amino-2vinylacetic acid (Ava) and (%,a)-divinylglycine (Dvg). The energy calculations have been made using molecular mechanics methods with a force field derived from MM2. The salient features are expressed in terms of conformational energy plots, drawn as a function of the backbone torsion angles $(Ci-1-Ni-C;-CI) and $(Ni-C;-CLN, + 1). The low-energy structures of these compounds are qualitatively consistent with the X-ray crystal structure analyses of peptides and peptidomimetics. They are also in agreement with the results of the solution-phase studies carried out by NMR and IR techniques. The results obtained have important implications in the design of conformationally restricted peptidomimetics. 0 Munksgaard 1995.

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Marked stereospecificity in a new class of anticonvulsants

Cited by 41 publications

References 11 publications

Anticonvulsant effects of isomeric nonimidazole histamine H<sub>3</sub> receptor antagonists

Anticonvulsant effects of isomeric nonimidazole histamine H<sub>3</sub> receptor antagonists

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

Conformational studies on model dipeptides of Gly, L ‐Ala and their C^α‐substituted analogs

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Marked stereospecificity in a new class of anticonvulsants

Cited by 41 publications

References 11 publications

Anticonvulsant effects of isomeric nonimidazole histamine H<sub>3</sub> receptor antagonists

Anticonvulsant effects of isomeric nonimidazole histamine H<sub>3</sub> receptor antagonists

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

Conformational studies on model dipeptides of Gly, L ‐Ala and their Cα‐substituted analogs

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Conformational studies on model dipeptides of Gly, L ‐Ala and their C^α‐substituted analogs