ABSTRACT
The x-ray crystal structure of 3-((5-methylisoxazol-3-yl)amino)-5-methylcyclohex-2-enone (12b) and 3-((5-methylisoxazolyl-3-yl)amino)-5,5-dimethylcyclohex-2-enone (12c) were determined and correlated to their anticonvulsant activity in mice and rats. A hypothesis for the toxicity of the analogs are advanced. In addition, a series of 5-methyl-N-(3-oxocyclohex-1-enyl)-isoxazole-3-carboxamides were synthesized and evaluated for anticonvulsant activity. These compounds were compared to the activity of the corresponding amino and aminomethyl enaminones. Additional investigation involved the synthesis and evaluation of a trifluoromethyl analog of the active isoxazole tert-butyl 4-(5-methisoxazol-3-yl-amino)-6-methyl-2-oxo-cyclohex-3-ene carboxylate (4f).
Subject(s)
Anticonvulsants/pharmacology , Anticonvulsants/toxicity , Cyclohexanones/pharmacology , Cyclohexanones/toxicity , Amides/chemistry , Animals , Anticonvulsants/chemistry , Cyclohexanones/chemistry , Hydrocarbons, Fluorinated/chemistry , Male , Mice , Rats , Structure-Activity RelationshipABSTRACT
For the title compound, C(13)H(14)ClNO(3)S, geometrical parameters, determined using X-ray diffraction techniques, are compared with those calculated by density functional theory (DFT), using hybrid exchange-correlation functional, B3LYP methods. The dihedral angle between the benzene ring and the conjugated part of the cyclo-hexene ring is 87.47â (5)°. The cyclo-hexene ring and its substituents are disordered over two conformations, with occupancies of 0.786â (3) and 0.214â (3). In the crystal, mol-ecules are linked into chains in the c-axis direction by inter-molecular N-Hâ¯O(C=O) hydrogen bonds. C-Hâ¯O inter-actions are also observed.
ABSTRACT
A small library of anilino enaminones was analyzed for potential anticonvulsant agents. We examined the effects of three anilino enaminones on neuronal activity of output neurons, mitral cells (MC), in an olfactory bulb brain slice preparation using whole-cell patch-clamp recording. These compounds are known to be effective in attenuating pentylenetetrazol-induced convulsions. Among the three compounds tested, 5-methyl-3-(4-trifluoromethoxy-phenylamino)-cyclohex-2-enone (KRS-5Me-4-OCF3) showed potent inhibition of MC activity with an EC50 of 24.5 µM. It hyperpolarized the membrane potential of MCs accompanied by suppression of spontaneous firing. Neither ionotropic glutamate receptor blockers nor a GABA(B) receptor blocker prevented the KRS-5Me-4-OCF(3)-evoked inhibitory effects. In the presence of GABA(A) receptor antagonists, KRS-5Me-4-OCF(3) completely failed to evoke inhibition of MC spiking activity, suggesting that KRS-5Me-4-OCF3-induced inhibition may be mediated by direct action on GABA(A) receptors or indirect action through the elevation of tissue GABA levels. Neither vigabatrin (a selective GABA-T inhibitor) nor 1,2,5,6-tetrahydro-1-[2-[[(diphenylmethylene)amino]oxy]ethyl]-3-pyridinecarboxylic acid hydrochloride (NNC-711) (a selective inhibitor of GABA uptake by GABA transporter 1) eliminated the effect of KRS-5ME-4-OCF3 on neuronal excitability, indicating that the inhibitory effect of the enaminone resulted from direct activation of GABA(A) receptors. The concentration-response curves for GABA are left-shifted by KRS-5Me-4-OCF3, demonstrating that KRS-5Me-4-OCF3 enhanced GABA affinity and acted as a positive allosteric modulator of GABA(A) receptors. The effect of KRS-5Me-4-OCF3 was blocked by applying a benzodiazepine site antagonist, suggesting that KRS-5Me-4-OCF3 binds at the classic benzodiazepine site to exert its pharmacological action. The results suggest clinical use of enaminones as anticonvulsants in seizures and as a potential anxiolytic in mental disorders.
Subject(s)
Anticonvulsants/chemistry , Anticonvulsants/pharmacology , Brain/drug effects , GABA Modulators/chemistry , GABA Modulators/pharmacology , Receptors, GABA-A/physiology , Action Potentials/drug effects , Action Potentials/physiology , Allosteric Regulation/drug effects , Allosteric Regulation/physiology , Animals , Anticonvulsants/metabolism , Brain/metabolism , GABA Modulators/metabolism , Mice , Mice, Inbred C57BL , Protein Binding/physiologyABSTRACT
3D-QSAR studies comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were carried out on 26 structurally diverse subcutaneous pentylenetetrazol (scPTZ) active enaminone analogues, previously synthesized in our laboratory. CoMFA and CoMSIA were employed to generate models to define the specific structural and electrostatic features essential for enhanced binding to the putative GABA receptor. The 3D-QSAR models demonstrated a reliable ability to predict the CLogP of the active anticonvulsant enaminones, resulting in a q(2) of 0.558 for CoMFA, and a q(2) of 0.698 for CoMSIA. The outcomes of the contour maps for both models provide detailed insight for the structural design of novel enaminone derivatives as potential anticonvulsant agents.
Subject(s)
Amines/chemistry , Anticonvulsants/chemistry , GABA Antagonists/chemistry , Quantitative Structure-Activity Relationship , Drug Design , Humans , Models, Molecular , Pentylenetetrazole , Receptors, GABA/chemistry , Receptors, GABA/metabolismABSTRACT
Enaminones, enamines of beta-dicarbonyl compounds, have been known for many years. Their early use has been relegated to serving as synthetic intermediates in organic synthesis and of late, in pharmaceutical development. Recently, the therapeutic potential of these entities has been realized. This review provides the background and current research in this area with emphasis of these agents as potential anticonvulsants, their proposed mechanisms of action, and as potential modulators of multidrug resistance (MDR).
