AMPA receptors modulators

Larson, J., Quach, C.N., LeDuc, B.Q. et al. Effects of an AMPA receptor modulator on methamphet-amine-induced hyperactivity. Brain Res. 738 353, 1996. 

With respect to recent patent applications the neuroprotective properties of non-NMDA antagonists are still in the focus of pharmacetical research, but the majority of patents does not propose that they should be used for pain relief. However, the continuing interest in AMPA/kainate receptor modulators might also lead to further investigations of their analgesic properties. Two examples of AMPA receptor modulators recently claimed for pain are shown. 

Engelman HS, Anderson RL, Daniele C, MacDermott AB (2006) Presynaptic alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors modulate release of inhibitory amino acids in rat spinal cord dorsal horn. Neuroscience 139 539 Engelman HS, MacDermott AB (2004) Presynaptic ionotropic receptors and control of transmitter release. Nat Rev Neurosci 5 135 45... 

Scheme 6.10 Asymmetric hydrogenation of an activated imine to yield the AMPA receptor modulator S 18986.

Compounds that positively modulate the AMPA receptor have been reviewed [146, 147]. The first reports of AMPA receptor modulators, appearing over 20 years ago, were plant lectins (e.g., concanavalin A) that inhibited rapid non-NMDA receptor desensitization [148]. Shortly after, the nootropic drug 12 (aniracetam) (Fig. 3), which was reported to effect learning and memory, was found to selectively... 

Marenco S, Weinberger DR (2006) Therapeutic potential of positive AMPA receptor modulators in the treatment of neuropsychiatric disorders. CNS Drugs 20 173-185... 

Phillips D, Sonnenberg J, Arai AC et al (2002) S -alkyl-benzothiadiazides a new subgroup of AMPA receptor modulators with improved affinity. Bioorg Med Chem 10 1229-1248... 

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... 

The 4-alkylated benzo-l-thia-2,4-diazine 1,1-dioxides 100 (R = H, Cl, NO2), AMPA receptor modulators, were prepared from 477-benzo-l-thia-2,4-diazine 1,1-dioxides 99 by alkylation with l-fluoro-2-iodoethane followed by reduction with NaBH4 in Pr OH (Equation 8) <2005EPP1557412>. 

Acid chlorides react with 2-aminobenzenesulfonamides to produce 4//-benzo-l-thia-2,4-diazine 1,1-dioxides, which are then reduced to yield 3,4-dihydro-2//-benzo-l-thia-2,4-diazine 1,1-dioxides such as 234 (R = C1, I, MeO, Ar, NH2, SO2NH2 R = cycloalkyl) as positive AMPA receptor modulators <1999W09942456>. C-3-Labeled thieno[3,2-r ]-l-thia-2,4-diazine 1,1-dioxide 235 has been made from the corresponding 3-aminothiophene-2-sulfon-amide and C-labeled ethyl chloroformate <2004JLR127>. 

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-... 

Benke TA, Luthi A, Isaac JTR, CoUingridge GL (1998) Modulation of AMPA receptor unitary conductance by synaptic activity. Nature 393 793-797... 

Reproduced, with permission, from Tomita et al Stargazin modulates AMPA receptor gating and trafficking by distinct domains. Nature 2005 435 1052.)... 

Cyr, M. Ghribi, O. Thibault, C. Morissette, M. Landry, M. di Paolo, T. Ovarian steroids and selective estrogen receptor modulators activity on rat brain NMDA and AMPA receptors. Brain Res. Rev. 2001, 37(1—3), 153—161. 

The role of non-NMDA receptor modulators in pain is not as clear as the role of NMDA receptors, but there is evidence to indicate that AMPA and kainate receptors may be involved in nociceptive processing. 

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