Conformational restriction glutamate

Fluorinated Conformationally Restricted Glutamate Analogues for CNS Drug Discovery and Development... 

In this chapter, the design strategy, synthesis, pharmacology, and pharmacokinetics of fluorinated conformationally restricted glutamate analogues are described in comparison with those of the corresponding hydrocarbon-based compounds. 

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. 

D. S. Radchenko, O. O. Grygorenko, I. V. Komarov, Tetrahedron Asymmetry 2008, 19, 2924—2930. Synthesis of conformationally restricted glutamic acid analogs based on the spiro[3.3]heptane scaffold. 

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. 

Fluorinated Conformation ally Restricted Glutamate Analogues 75... 

On the other hand, cyclic L-glutamic acid derived enones 15 and 17 are converted into the desired cyclopropane derivatives 16 and 18 with high diastereofacial selectivity50. Both intermediates are of interest for the preparation of conformationally restricted analogs of L-glutamic acid. 

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. 

Fig. 1. Molecular structures of conformationally restricted excitatory analogs of L-glutamic acid.

From the neurophysiologic and ligand-binding studies, it is apparent that there are a number of receptors that mediate the excitatory effects of acidic amino acids and their conformationally restricted or synthetic analogs. As noted by Watkins (1978), the flexibility of the linear acidic amino acids such as glutamic acid may allow them to assume a variety of conformations capable of binding to subpopulations of these receptors, some of which are selectively activated by the conformationally restricted analogs. While neuronal excitation appears to be a property common to all the acidic amino acids, specific receptors could also activate distinct sets... 

Johnston, G. A. R., Curtis, D. R., Davies, J., and McCulloch, R. M., 1974, Spinal interneurone excitation by conformationally restricted analogues of L-glutamic acid, Nature 248 804-805. 

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