Abstract
In an ongoing effort to identify novel drugs that can be used as neurotherapeutic compounds, we have focused on anilino enaminones as potential anticonvulsant agents. Enaminones are organic compounds containing a conjugated system of an amine, an alkene and a ketone. Here, we review the effects of a small library of anilino enaminones on neuronal activity. Our experimental approach employs an olfactory bulb brain slice preparation using whole-cell patch-clamp recording from mitral cells in the main olfactory bulb. The main olfactory bulb is a key integrative center in the olfactory pathway. Mitral cells are the principal output neurons of the main olfactory bulb, receiving olfactory receptor neuron input at their dendrites within glomeruli, and projecting glutamatergic axons through the lateral olfactory tract to the olfactory cortex. The compounds tested are known to be effective in attenuating pentylenetetrazol (PTZ) induced convulsions in rodent models. One compound in particular, KRS-5Me-4-OCF3, evokes potent inhibition of mitral cell activity. Experiments aimed at understanding the cellular mechanism underlying the inhibitory effect revealed that KRS-5Me-4-OCF3 shifts the concentration-response curve for GABA to the left. KRS-5Me-4-OCF3 enhances GABA affinity and acts as a positive allosteric modulator of GABAA receptors. Application of a benzodiazepine site antagonist blocks the effect of KRS-5Me-4-OCF3 indicating that KRS-5Me-4-OCF3 binds at the classical benzodiazepine site to exert its pharmacological action. This anilino enaminone KRS-5Me-4-OCF3 emerges as a candidate for clinical use as an anticonvulsant agent in the battle against epileptic seizures.
Highlights
In an ongoing effort to identify novel drugs that can be used as neurotherapeutic compounds, we have focused on anilino enaminones as potential anticonvulsant agents
We review the cellular effects of a small library of anilino enaminones on a key output neuron in a brain slice preparation containing the main olfactory bulb, which was used as an experimental platform to study enaminones
The main olfactory bulb is anatomically different from those two brain regions and provides three advantages to test the cellular mechanisms of the effects of anilino enaminones [14,15]
Summary
Enaminones are the enamines of β-dicarbonyl compounds that comprised an amino group linked through a carbon-carbon double bond to a keto group (HN-C=C-C=O). [1]. A diverse series of anilino enaminones was recently synthesized and investigated as potential anticonvulsant compounds These compounds are structurally unique compared to currently available antiepileptic drugs [3,4,5,6,7,8]. The scPTZ seizure model identifies compounds that inhibit the GABA antagonistic effects of pentylenetetrazol or raise the seizure threshold [9] In terms of their anticonvulsant activities, anilino enaminones are comparable to some clinically used agents in animal models of seizures. Mitral cells in an acute slice preparation of the main olfactory bulb serve as a good model for testing the bioactivity of enaminone compounds and to explore the mechanisms underlying their activity. The effects of three anilino enaminones on neuronal activity of output neurons, mitral cells, in an olfactory bulb brain slice preparation using whole-cell patch-clamp recording has been examined. We will first review the structural and functional organization of the main olfactory bulb, before describing the modulation of mitral cell activity by anilino enaminones
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