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Structural Features of ATPA and Thio-ATPA—Potent and Selective GluR5 Receptor Agonists. Crystal Structure Determinations and Quantum Chemical Calculations

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Abstract

ATPA and thio-ATPA are semirigid analogs of the excitatory neurotransmitter (S)-glutamic acid. (S)-ATPA and (S)-thio-ATPA are potent and selective GluR5 receptor agonists. X-ray structure determination of the zwitterions of (RS)-ATPA and (R)-thio-ATPA has been performed. Furthermore, quantum chemical ab initio calculations have been carried out on the tautomeric heterocyclic substructures 4,5-dimethyl-3-isoxazolol and 4,5-dimethyl-3-isothiazolol. Very high level ab initio calculations (including triple-ζ basis set and treatment of electron correlation) are necessary for a consistent theoretical description of the heterocyclic rings of these compounds. Results for the aqueous phase properties (PB-SCRF method, combined with density functional theory) are chemically reasonable and in agreement with experimental data. While the 3-isoxazolol tautomer of the zwitterionic amino acid ATPA predominates in all phases, the 3(2H)-isothiazolone tautomer of the zwitterionic amino acid thio-ATPA predominates in the crystal structure (3:1) and most likely in weakly acidic aqueous solution.

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Authors and Affiliations

  1. PharmaBiotec Research Center, Department of Medicinal Chemistry, The Royal Danish School of Pharmacy, Universitetsparken 2, DK-2100, Copenhagen, Denmark

    Karla Frydenvang, Jeremy R. Greenwood, Stine B. Vogensen & Lotte Brehm

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  1. Karla Frydenvang
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  2. Jeremy R. Greenwood
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  3. Stine B. Vogensen
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  4. Lotte Brehm
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Frydenvang, K., Greenwood, J.R., Vogensen, S.B. et al. Structural Features of ATPA and Thio-ATPA—Potent and Selective GluR5 Receptor Agonists. Crystal Structure Determinations and Quantum Chemical Calculations. Structural Chemistry 13, 479–490 (2002). https://doi.org/10.1023/A:1020569622239

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