Structure of lamotrigine methanol solvate: 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine–methanol, a novel anticonvulsant drug

Janes, Robert W.; Lisgarten, J. N.; Palmer, R. A.

doi:10.1107/s0108270188010224

Cited by 24 publications

(18 citation statements)

References 1 publication

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“…Atoms O11, C32, C34 and C35 of the dimethylformamide solvent molecule are disordered over two sites with occupancies of 0.73 (1) and 0.27 (1). In all essential details, the molecular geometry (Table 1) is in good agreement with that of similar structures (Janes et al, 1989;Potter et al, 1999;Kubicki & Codding, 2001).…”

Section: Commentsupporting

confidence: 71%

Lamotriginium benzoate dimethylformamide solvate

Sridhar

Ravikumar

2005

Acta Cryst E

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Section: Commentsupporting

confidence: 71%

Lamotriginium benzoate dimethylformamide solvate

Sridhar

Ravikumar

2005

Acta Cryst E

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“…The crystal coordinates for lamotrigine (46) were docked into this model using the program AUTODOCK. The highest ranking docked position has a final energy of Ϫ4.29 kcal/mol and on analysis gave consistent results with respect to the mutation studies.…”

Section: Model Of the Sodium Channel Pore And Its Interactions With Lmentioning

confidence: 99%

Binding of the Anticonvulsant Drug Lamotrigine and the Neurotoxin Batrachotoxin to Voltage-gated Sodium Channels Induces Conformational Changes Associated with Block and Steady-state Activation

Cronin

O’Reilly

Duclohier

et al. 2003

Journal of Biological Chemistry

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Voltage-gated sodium channels are dynamic membrane proteins characterized by rapid conformational changes that switch the molecule between closed resting, activated, and inactivated states. Sodium channels are specifically blocked by the anticonvulsant drug lamotrigine, which preferentially binds to the channel pore in the inactivated open state. Batrachotoxin is a lipidsoluble alkaloid that causes steady-state activation and binds in the inner pore of the sodium channel with overlapping but distinct molecular determinants from those of lamotrigine. Using circular dichroism spectroscopy on purified voltage-gated sodium channels from Electrophorus electricus, the secondary structures associated with the mixture of states present at equilibrium in the absence of these ligands were compared with specific stabilized states in their presence. As the channel shifts to open states, there appears to be a significant change in secondary structure to a more ␣-helical conformation. The observed changes are consistent with increased order involving the S6 segments that form the pore, the domain III-IV linker, and the P-loops that form the outer pore and selectivity filter. A molecular model has been constructed for the sodium channel based on its homology with the pore-forming regions of bacterial potassium channels, and automated docking of the crystal structure of lamotrigine with this model produces a structure in which the close contacts of the drug are with the residues previously identified by mutational studies as forming the binding site for this drug.Voltage-gated sodium channels play an important physiological role in excitable membranes, underlying action potential initiation and propagation in nerves and muscles (1). They are also involved in a number of pathophysiologies, e.g. rhythm dysfunctions in the heart (2), and channelopathies (3, 4) due to inherited mutations, including hyperkaleimic periodic paralysis, myotonia congenita, and Long QT syndrome. Although their functions have been extensively characterized via electrophysiology (5), structural studies remain scanty, and the molecular basis of the central process of gating is still elusive despite recent progress (6).Sodium channels show strong sequence conservation across species and tissue-specific types (7). The sodium channel from the electric eel electroplax is 60% identical with that of voltagegated sodium channels from human muscle. The patterns of hydrophobicity and homologous residues are even more closely preserved, and this indicates that their three-dimensional structures will be very similar. The primary structure of the sodium channel from Electrophorus electricus was deduced from its cDNA sequence (8) and revealed the protein to consist of 1820 amino acids, producing a molecular mass of 208 kDa. There are also extensive sugar moieties covalently linked to the protein on its external face, making the total molecular mass of the channel ϳ260 -270 kDa (9). Its sequence contains four highly homologous internal repeats (domains I-IV), each of whi...

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“…Aa (Janes et al, 1989)] of the lamotrigine base have been reported previously, but no coordinates were deposited in the Cambridge Structural Database [Allen, 2002;refcode EFEMUX (Janes et al, 1989)]. The earlier reported unit cell appears to differ significantly from that found here.…”

Section: Commentmentioning

confidence: 55%

Lamotrigine, an antiepileptic drug, and its chloride and nitrate salts

Sridhar¹,

Ravikumar²

2009

Acta Crystallogr C Cryst Struct Commun

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In lamotrigine [systematic name: 6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine], C(9)H(7)Cl(2)N(5), (I), the asymmetric unit contains one lamotrigine base molecule. In lamotriginium chloride [systematic name: 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazin-2-ium chloride], C(9)H(8)Cl(2)N(5)(+).Cl(-), (II), the asymmetric unit contains one lamotriginium cation and one chloride anion, while in lamotriginium nitrate, C(9)H(8)Cl(2)N(5)(+).NO(3)(-), (III), the asymmetric unit contains two crystallographically independent lamotriginium cations and two nitrate anions. In all three structures, N-H...N hydrogen bonds form an R(2)(2)(8) dimer. In (I) and (II), hydrophilic layers are sandwiched between hydrophobic layers in the crystal packing. In all three structures, hydrogen bonds lead to the formation of a supramolecular hydrogen-bonded network. The significance of this study lies in its illustration of the differences between the supramolecular aggregation in the lamotrigine base and in its chloride and nitrate salts.

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Structure of lamotrigine methanol solvate: 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine–methanol, a novel anticonvulsant drug

Cited by 24 publications

References 1 publication

Lamotriginium benzoate dimethylformamide solvate

Lamotriginium benzoate dimethylformamide solvate

Binding of the Anticonvulsant Drug Lamotrigine and the Neurotoxin Batrachotoxin to Voltage-gated Sodium Channels Induces Conformational Changes Associated with Block and Steady-state Activation

Lamotrigine, an antiepileptic drug, and its chloride and nitrate salts

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