AMPA receptors allosteric modulators

Fernandez MC, Castano A, Dominguez E et al (2006) A novel class of AMPA receptor allosteric modulators. Part 1 design, synthesis, and SAR of 3-aryl-4-cyano-5-substituted-heteroaryl-2-carboxylic acid derivatives. Bioorg Med Chem Lett 16 5057-5061... 

The first allosteric modulators discovered to act on AMPA/KA receptors were the plant lectins, including concanavalin A (ConA), that block receptor desensitization, probably through binding to Y-1 inked oligosaccharides (51,52). It was soon discovered that certain benzothiazides, such as diazoxide and cyclothiazide, also act on the same allosteric site controlling non-NMDA receptor desensitization (53-55). Interestingly, ConA and cyclothiazide show high selectivity for KA and AMPA receptors, respec-... 

Ruel J., Guitton M. J., and Puell J. L. (2002). Negative allosteric modulation of AMPA-preferring receptors by the selective isomer GYKI 53784 (LY303070), a specific non-competitive AMPA antagonist. CNS Drug Rev. 8 235-254. 

Because AMPA receptors function in concert with NMDA receptors, they have been proposed as alternative therapeutic targets in schizophrenia. AMPAkines function as positive allosteric modulators of AMPA receptor-mediated neurotransmission, and facilitate learning and memory in both human (Ingvar et al., 1997) and animal (Hampson et al., 1998) models. Further, these drugs act synergistically with antipsycho-tics to reverse amphetamine-induced hyperactivity (Johnson et al., 1999). 

Ahmed AH, Oswald RE (2010) Piracetam defines a new binding site for allosteric modulators of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors. J Med Chem 53 2197-2203... 

Francotte P, Tullio P, Goffin E et al (2007) Design, synthesis, and pharmacology of novel 7-substituted 3, 4-dihydro-2H-l, 2, 4-benzothiadiazine 1, 1-dioxides as positive allosteric modulators of AMPA receptors. J Med Chem 50 3153-3157... 

Harpsoe K, Liljefors T, Balle T (2008) Prediction of the binding mode of biarylpropylsulfo-namide allosteric AMPA receptor modulators based on docking, GRID molecular interaction fields and 3D-QSAR analysis. J Mol Graph Model 26 874-883... 

Pei XF, Sturgess MA, Valenzuela CF et al (1999) Allosteric modulators of the AMPA receptor novel 6-substituted dihydrophthalazines. Bioorg Med Chem Lett 9 539-542... 

Macchiarulo A, De Luca L, Costantino G et al (2004) QSAR study of anticonvulsant negative allosteric modulators of the AMPA receptor. J Med Chem 47 1860-1863... 

The pyrido analogs of 4/f-benzo-l-thia-2,4-diazine 1,1-dioxides, that is, 95, are alkylated at N-4 using an alkyl halide (R = Me, Et, Pr ) with K2GO3 as base (Equation 6). The products, 96, are useful as positive allosteric modulators of AMPA receptors <1998JME2946>. 

Orthoformates react with pyrido aminosulfonamides such as 230 to produce the corresponding 4//-l-thia-2,4-diazine 1,1-dioxides 231 (R = H, Me) (Equation 54) <1998JME2946, 2003S1603>. These compounds ate reduced readily to the 3,4-dihydro-2/7-pyrido-l-thia-2,4-diazine 1,1-dioxide derivatives (see Section 9.05.6.2.4), which are of significant interest as positive allosteric modulators of AMPA receptors <2001W02001040210, 2004ERP2854634>. 

The Barton-Zard reaction found its application in the synthesis of LY2059346, a positive allosteric modulator of the a-amino-3-hydroxyl-L-aspartate (AMPA) receptor as a potential treatment of neurological and psychiatric disorders. ... 

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