Synthesis, neuronal activity and mechanisms of action of halogenated enaminones.

Abstract:

:Due to the excellent anticonvulsant activity of previously synthesized halogenated enaminones, more disubstituted analogs were synthesized and evaluated in vitro. The new enaminones either had no effect, depressed, or enhanced population spike (PS) amplitude in the rat hippocampus in a concentration-dependent manner. Structure-activity relationship (SAR) analysis indicated that compounds 21 and 25 (with dibromo substituents) were equipotent, and more potent than compound 2 (with dichloro substituents), with compound 25 being the most efficacious of all tested compounds. Both diiodo derivatives 30 and 31 tested produced no significant effect on PS. For PS depression, phenyl substitution on the cyclohexenone ring produced the most efficacious compound 25. PS depressing analogues also depressed evoked excitatory postsynaptic current (EPSC) and action potential firing frequency. Removal of phenyl or methyl group from position 6 on the cyclohexenone ring of enaminone esters produced compound 28 which exhibited pro-convulsant effects. There was no direct correlation between C log P values and anticonvulsant activity of the halogenated enaminones. The mechanisms of anticonvulsant activity were the indirect suppression of excitatory synaptic transmission by enhancing extracellular GABA, and the direct suppression of action potential firing of the neurons.

journal_name

Eur J Med Chem

authors

Edafiogho IO,Qaddoumi MG,Ananthalakshmi KV,Phillips OA,Kombian SB

doi

10.1016/j.ejmech.2014.02.002

subject

Has Abstract

pub_date

2014-04-09 00:00:00

pages

20-30

eissn

0223-5234

issn

1768-3254

pii

S0223-5234(14)00122-6

journal_volume

76

pub_type

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