Glutamate analogs agonists

Glutamic and aspartic acids, which are viewed as excitatory neurotransmitter amino acids, are present in the CNS in relatively large amounts. Kainic acid, which is viewed as a rigid and therefore conformationally restricted glutamate analog, has been proposed as an agonist of it, if not as a direct receptor activator, then by sensitizing these receptors to glu by some allosteric interaction. 

The single recently published application of the amide form was in the synthesis of the histone deacetylase inhibitor vorinostat (1691 (Figure 6.52). Phosphonium salt 166 was prepared by the reaction of triphenylphosphine with chloro[l- C]acetanilide, itself prepared via chloro [l- " C]acetyl chloride. Olefination of aldehyde 167 with the yhde produced from 166 furnished the a,/3-unsaturated amide 168 in 85% yield °. The tributylphosphonium analog was employed as a starting material for the synthesis of [ " C]GV 1550526, a glutamate co-agonist . 

Further developments demonstrated that the 4,4-diphenyl-3-butenyl moiety could be replaced by ether-type analogs °° ° and that the attachment of a lipophilic 3,3-diphenylpropyl side chain can take place at the carbon atom at the 6-position of the amino acid. ° However in this latter case, despite an reasonable in vitro activity (/C50 = lOOnM), no in vivo activity is observed. Final optimization of SKF 89976A led to the bis-thiophene tia-gabine. In a similar way, w,w-dipheny 1-alkyl chains (butterflies) were also attached to L-glutamic acid to yield glutamate metabotropic m3 receptor-selective agonists. ... 

Conformationally restricted analogs of other low molecular mass agonists have been synthesized or discovered in attempts to characterize the bioactive conformation of the ligand., This field is vast and selected examples of constrained agonist analogs of dopamine (23.10) versus (23.11), GABA (23.12) versus (23.13)-(23.14),2 glutamic acid (23.15) versus (23.16) and (23.17), histamine (23.18) versus (23.19) and (23.20), serotonin (23.21) versus (23.22) that have been discovered by application of this approach are shown in Fig. 23.2. 

The conformationally restricted glutamic acid analog LY404039 (1) was recently found to be a selective agonist for metabotropic glutamate 2/3 (mGlu2/3) receptors and has shown antipsychotic potential in animal studies. In order to fuel further development, a scalable and robust synthetic route for the 8-step synthesis of 1 from thiophene was developed and successfully implemented on 60-70 kg pilot-plant scale. 

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