Positive and negative AMPA receptor modulators based on tricyclic bispidine derivative: Minor structural change inverts the type of activity |
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| Affiliation: | 1. Department of Chemistry, M. V. Lomonosov Moscow State University, 119991 Moscow, Russian Federation;2. Institute of Physiologically Active Compounds, Russian Academy of Sciences, 142432 Chernogolovka, Moscow Region, Russian Federation |
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| Abstract: | Two new potent AMPA receptor allosteric modulators, 6-(1,3-benzodioxol-5-yl)-1,11-dimethyl-3,6,9-triazatri-cyclo[7.3.1.13,11]tetradecane-4,8,12-trione and -4,8-dione were synthesized from 1,3-benzodioxol-5-amine and the corresponding 3,7-dichloroacetyl-3,7-diazabicyclo[3.3.1]-nonanes. In a wide concentration range (10?12–10?7 m), the 12-oxo derivative acts as a positive modulator causing the potentiation of the kainate-induced AMPA receptor currents with maximum potentiation at 1 nm (62%) while its analogue without a ketone group has significant (up to 40%) negative modulator effect. Their tentative mechanisms of action were analyzed by means of molecular modelling |
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| Keywords: | 3,7-diazabicyclo[3.3.1]nonane bispidines heterocyclization AMPA receptors allosteric modulators |
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