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Convergent Synthesis and Pharmacology of Substituted Tetrazolyl-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid Analogues

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journal contribution
posted on 05.05.2005, 00:00 by Stine B. Vogensen, Rasmus P. Clausen, Jeremy R. Greenwood, Tommy N. Johansen, Darryl S. Pickering, Birgitte Nielsen, Bjarke Ebert, Povl Krogsgaard-Larsen
The synthesis and pharmacological characterization of 1- and 2-alkyltetrazolyl analogues of (RS)-2-amino-3-[3-hydroxy-5-(2-methyl-2H-5-tetrazolyl)-4-isoxazolyl]propionic acid (2-Me-Tet-AMPA), a highly potent and selective agonist at AMPA receptors, are presented. A shorter and more convergent synthetic route than previously described, employing a new method for introducing the amino acid moiety, was developed for these derivatives. The 2-substituted isomers were selective agonists, and their activity correlated inversely with the size of the substituent. Structural explanations of the structure−activity relationship are provided.