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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 wholecell 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-OCF 3 ) showed potent inhibition of MC activity with an EC 50 of 24.5 M. 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-OCF 3 -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-OCF 3 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-OCF 3 , demonstrating that KRS-5Me-4-OCF 3 enhanced GABA affinity and acted as a positive allosteric modulator of GABA A receptors. The effect of KRS-5Me-4-OCF 3 was blocked by applying a benzodiazepine site antagonist, suggesting that KRS-5Me-4-OCF 3 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.

The enaminones represent potentially useful agents for the clinical treatment in generalized tonic-clonic seizures (Epilepsia, 1993, 34(6), 1141-1145, Biopharm. Drug Disp. 2003, 397-407). A regression analysis was performed to provide a quantitative structure-activity relationship (QSAR) correlation model for prediction of activity for the anticonvulsant enaminones. Molecular modeling was performed to determine the molecular confluence of the Unverferth model (J. Med. Chem. 1998, 41, 63-73) to the enaminones. Conclusions related to the sodium channel model were assessed.

Abstract3D 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 CLog P 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.

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