Gabaculin

Hydroxylysine (328) was synthesized by chemoselective reaction of (Z)-4-acet-oxy-2-butenyl methyl carbonate (325) with two different nucleophiles first with At,(9-Boc-protected hydroxylamine (326) under neutral conditions and then with methyl (diphenylmethyleneamino)acetate (327) in the presence of BSA[202]. The primary allylic amine 331 is prepared by the highly selective monoallylation of 4,4 -dimethoxybenzhydrylamine (329). Deprotection of the allylated secondary amine 330 with 80% formic acid affords the primary ally-lamine 331. The reaction was applied to the total synthesis of gabaculine 332(203]. 

The regioselectivity during hydride abstraction afforded by an ester substituent attached to cyclohexa-diene has also been exploited for total synthesis. The synthesis of (+)- and (-)-gabaculine in homochiral... 

A synthetic isomer of gabaculine (VII Fig. 8) has similar biochemical activity in vitro and in vivo (21) to gabaculine (22). 

The remaining isomer of gabaculine (VIII Fig. 8) has recently been synthesized and awaits testing (23). 

This method has been used for synthesis (equation II) of ( )-gabaculine (5), a naturally occurring amino acid involved in metabolism of y-aminobutyric acid. An... 

Whereas ammonia is an unsuitable nucleophile towards 7r-allylpalladium complexes, primary amines often participate well. Benzylamine and 4,4 -dimethoxybenzhydrylamine are especially useful, since subsequent removal of the benzylic substituents permits their use as ammonia equivalents. Such a deblocking procedure was used in a short synthesis of the enzyme inhibitor gabaculine from amino ester 1118. An allyl carbonate can be successfully employed as a substrate for palladium(0)-catalyzed animation to give 1219,20, but experimental difficulties have been experienced with a structurally similar carbonate9. As shown by the formation of 1016 and by the partial production of 13 prior to basic hydrolysis16, additional attack on an ester function may occur. Amino alcohols 13, formed with complete regioselectivity due to steric reasons, have been efficiently converted into isoquinuclidines16. 

It is conceivable that instead of hydrolysis of the imine intermediate 22 to give diamine 21 and PLP followed by formation of the alternative imine 24, an intramolecular transfer of the pyridoxyl moiety from one nitrogen to the other occurs via a five-membered ring intermediate 23. This appears not to be the case, however, as it would mean that free PLP is never formed and yet the enzyme is known to be inactivated by a number of suicide inhibitors, such as gabaculine, which react specifically with PLP [ 1,2,13]. 

The Km of the enzyme for GABA was lO M at 25°C. The enzyme was generally freshly prepared although it could be stored at -20°C dissolved in 0.1M Hepes buffer (pH 7.1) containing 5 mM dithiothreitol (DTT) for up to 2 weeks without appreciable loss of activity. Gabaculine and other inhibitors were usually prepared at... 

The inhibition data for the aminooxy acids was treated similarly (Table I). For the series of aminooxy acids ranging from the acetate to the valerate, and for gabaculine, there was little change in kcat (range from 0.11 to 0.18 sec ) whereas there was a 210-fold range of values of K[Pg.130]

Figure 2 Semi-log plot of the change in 6ABA-T activity in the presence of gabaculine, at 5X10 5M (two experiments) and 10 4M with time, showing first order kinetics.

Protective Effect of Gabaculine In Vivo Against Ethvl Aminooxvbutvrate (Compound 61... 

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