TY - JOUR

T1 - Structural features of ATPA and thio-ATPA - Potent and selective gluR5 receptor agonists. Crystal structure determinations and quantum chemical calculations

AU - Frydenvang, Karla

AU - Greenwood, Jeremy R.

AU - Vogensen, Stine B.

AU - Brehm, Lotte

N1 - Funding Information: This work was supported by grants from the Alfred Benzon Foundation, the Lundbeck Foundation, the NSW Centre for Parallel Computing, and the Danish Natural Science Research Council. We gratefully acknowledge the technical assistance of Søren C. Schou for crystallizing (RS)-ATPA, Flemming Hansen, Department of Chemistry, University of Copenhagen, with the collection of X-ray data, Tine B. Stensbøl for donating the thio-ATPA sample, and Professors Povl Krogsgaard-Larsen and Tommy Liljefors for valuable discussions.

PY - 2002/12

Y1 - 2002/12

N2 - 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.

AB - 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.

KW - ab initio calculations

KW - ATPA

KW - GluR5 receptor agonist

KW - tautomerism

KW - Thio-ATPA

KW - X-ray structure

UR - http://www.scopus.com/inward/record.url?scp=1842536812&partnerID=8YFLogxK

U2 - 10.1023/A:1020569622239

DO - 10.1023/A:1020569622239

M3 - Journal article

AN - SCOPUS:1842536812

VL - 13

SP - 479

EP - 490

JO - Structural Chemistry

JF - Structural Chemistry

SN - 1040-0400

IS - 5-6

ER -