GABA analogues

Figure 11.4 Blockers of GABA transport.The upper panel shows the structure of several GABA analogues that inhibit GABA transport into neurons or glia (see text). The lower panels show more recently developed compounds that exhibit selectivity for various cloned GABA transporters...

The N-silylated aminomethylcyclopropenecarboxylic ester underwent a smooth highly endo- and anti-selective [4+2]-cycloaddition with cyclopentadiene [2]. The novel GABA analogue 5 can be liberated in good yield by acid treatment [6]. 

Baxendale IR, Ley SV, Ernst M, Krahnert W-R (2002e) Application of polymer-supported enzymes and reagents in the synthesis of y-aminobutyric acid (GABA) analogues. Synlett 1641-1644... 

Krogsgaard-Larsen, P Hjeds, H Curtis, D. R Lodge, D., and Johnston, G. A. R. (1979) Dihydromuscimol, thiomuscimol and related heterocyclic compounds as GABA analogues. J. Neurochem. 32,1717-1724. 

Bolvig, T., Larsson, O. M., Pickering, D., Nelson, N., Falch, E., Krogsgaard-Larsen, P., and Schousboe, A. (1999) Action of bicyclic isoxazole GABA analogues on GABA transporters and its relation to anticonvulsant activity. Eur. J. Pharmacol. 375, 361-31 A. 

Schousboe, A. (1979) Effects of GABA-analogues on the high-affinity uptake of GABA in astrocytes in primary cultures. Adv. Exp. Med. Biol. 123, 219-237. 

Matheson, G. K., Freed, E., and Tunnicliff, G. 1986. Novel GABA analogues as hypotensive agent. Neuropharmacology 25,1191-1195. 

The consistency of the high levels of enantiocontrol accessible in these diazoester cyclizations is underpinned by their growing applications in enantiose-lective synthesis of bioactive molecules containing cyclopropane units. Notable examples include the preparation of multifunctional cyclopropanes as peptide isosteres for renin inhibitors (Scheme 4) [42] presqualene alcohol from farnesyl diazoacetate (Scheme 5) [43] the GABA analogue 3-azabicyclo[3.1.0]hexan-2-one from N-allyldiazoacetamide, Eq. (26) [23] and precursors of lR,3S)-cis-chrysanthemic acid and the pheromone, E-(-)-dictyopterene C (Scheme 6) [44, 45],... 

Gabapentin was designed as a GABA analogue and is an effective anticonvulsant but it does not work on GABA receptors. 

Various 7-aminobutyric acid (GABA) analogues, among them cis- and trans-2-AC C, were investigated as potential inhibitors of the GABA uptake in brain synaptosomes and in synaptic membrane vesicles [180-182]. cis-2-ACPC was found to be a potent inhibitor of the GABA uptake in the synaptosomes. The trans counterpart proved to be half as potent as the cis isomer [182]. 

A redox system (50/51) to affect brain delivery of y-aminobutyric acid (GABA) derivatives and analogues was also developed. Zincke reaction of 41 with acetal 49 followed by dithionite reduction afforded the 1,4-dihydropyridine prodrug 50, which was hydrolyzed and oxidized in vivo to the active GABA analogue 51. The neutral and lipophilic 1,4-dihydropyridine 50 can penetrate the blood-brain barrier (BBB), whereas the oxidized pyridinium salt 51 is retained in the brain for an extended period and then eliminated. 

The only GABA analogue that has yet found a place in human medicine is... 

Brandt NJ, et al. Treatment of glutaryl-CoA dehydrogenase deficiency (glutaric aciduria). Experience with diet, riboflavin, and GABA analogue. J Pediatr. 1979 94(4) 669-73. 

Larsson O M, Thorbek P, Krogsgaard-Larsen P, and Schousboe A. (1981) Effects of homo-p-prolme and other heterocyclic GABA analogues on GABA uptake in neurons and astroglial cells and GABA receptor binding. / Neurochem 37, 1509-1516. 

Barker, J. L., and Mathers, D. A., 1981, GABA analogues activate channels of different duration on cultured mouse spinal neurone. Science 212 358-361. 

Fig. 9.19. ReNDeR plot of GABA analogues ( potent agonist A weak agonist no agonist activity) described by 33 properties (from Livingstone et at. 1991, copyright 1991...

Fig. 9.22. Non-linear map of 17 GABA analogues described by seven physicochemical properties (from A-Razzak and Glen 1992, copyright (1992) Wellcome Foundation and...

An alternative method for the synthesis of tran -alkenyl /f-phosphinates involved AIBN initiated radical addition of ethyl phosphinate to alkenes and alkynes. The method was applied to the preparation of GABA analogues. A new route to chiral phospholanes has been presented. Enantiomerically pure P-chiral dicyclohexyl-ammonium 2-(phosphinyl)acrylates (236) have been obtained by an asymmetric Michael reaction with imine, which opens a new general route to the enantioselective synthesis of a-methylene-6-valerolactones (237) (Scheme 97). ... 

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