Positive and negative AMPA receptor modulators based on tricyclic bispidine derivative: Minor structural change inverts the type of activity

• Published in: Mendeleev communications Vol. 32; no. 3; pp. 360 - 363
• Main Authors: Lavrov, Mstislav I., Veremeeva, Polina N., Golubeva, Elena A., Radchenko, Eugene V., Zamoyski, Vladimir L., Grigoriev, Vladimir V., Palyulin, Vladimir A.
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 01.05.2022
• Subjects: 3,7-diazabicyclo[3.3.1]nonane; allosteric modulators; AMPA receptors; bispidines; heterocyclization; heterocyclization; 3,7-diazabicyclo[3.3.1]nonane; AMPA receptors; bispidines; allosteric modulators
• ISSN: 0959-9436
• DOI: 10.1016/j.mencom.2022.05.023

[Display omitted] 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