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Design and Synthesis of New Glutamic Receptor Ligands

Lennart Bunch

(S)-Glutamic acid (Glu) is the major excitatory neurotransmitter activating the Glu receptors (GluR) in the central nervous system (CNS). The Glu receptors are involved in important physiological functions such as memory, cognitive mechanisms and thus a number of patophysiological processes such as Alzheimer's disease, Parkinson's disease, Huntingston's chorea, amyotrophic lateral sclerosis, AIDS dementia and epilepsy.

This Ph.D.-dissertation describes three independent projects within the area: Design and synthesis of novel Glu analogues. The project first presented aimed at the synthesis of four 4-alkylidene Glu analogues. The target compounds were designed on the basis of the two ligands 2-amino-3-(5-tert-butyl-3-hydroxy-4-isoxazolyl)propionic acid (ATPA) and (2S,4R)-4-methyl Glu. A pharmacological study of the four synthesized compounds revealed selectivity for the iGluR5 subtype. The second project aimed at the synthesis of thioibotenic acid - a sulfur analogue of the naturally occurring neurotoxin ibotenic acid. To achieve a highly convergent synthesis of thioibotenic acid, new synthetic methodology was developed for functionalization of the 3-oxygenated isothiazole parental system. In pharmacological assays, thioibotenic acid showed an unexpected high affinity for the mGluR4 subtype compared with ibotenic acid. The third and last project aimed at the design and synthesis of (1S,3S,4R,5S)-3,5-dicarboxy-2-azanorbornane (3S-DCAN) - a rationally designed, highly conformationally restricted Glu analogue. The conformation that kainic acid adopts when crystallized in an iGluR2 construct, was used in the design phase. Four different multi step synthetic approaches were attempted of which only one led to the successful synthesis of racemic DCAN. Preliminary pharmacological investigations showed that racemic DCAN did not have affinity for the iGlu receptors nor showed activity at the mGlu receptors.

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