title: Conformational analysis and molecular modelling of a partial GABAA agonist and a glycine antagonist related to the GABAA agonist, THIP.
abstract: A series of 3-hydroxyisoxazoles (3-isoxazoles) substituted in the 5-position by piperidyl moieties (2-, 3-, and 4-PIOL) were studied by molecular modelling and computer graphics methods. Whereas 2-PIOL is pharmacologically inactive, 3-PIOL is a glycine antagonist and 4-PIOL a low-efficacy partial GABAA agonist. A conformational analysis of the isomeric PIOLs was performed on the basis of molecular mechanics calculations. The conformational analysis revealed a large degree of conformational freedom for all three compounds, especially of conformers having the 3-hydroxyisoxazole moiety in equatorial positions. By comparison of the PIOLs with the semi-rigid GABAA agonist THIP and the conformationally restricted glycine antagonist THAZ, the conformations relevant for GABAA and glycine receptor recognition were determined. For 2-PIOL a predicted active conformation is energetically favourable, but it exhibits considerable extra volume as compared to THIP, which may explain its lack of affinity for GABAA receptors. 3-PIOL is capable of adopting a conformation resembling that of THAZ. The GABAA receptor affinity of 4-PIOL may be explained by its ability to orientate the functional groups in space in a manner that allows a comparison with THIP. The low efficacy and affinity of 4-PIOL may reflect that not all atoms are directly involved in receptor binding. Certain steric requirements for binding to the GABAA receptor site have been identified and discussed.
authors.affiliation: PharmaBiotec Research Center, Royal Danish School of Pharmacy, Department of Organic Chemistry, Universitetsparken 2, Copenhagen.
authors.forename: J R
authors.initials: JR
authors.lastname: Buur
authors.forename: H
authors.initials: H
authors.lastname: Hjeds
authors.forename: P
authors.initials: P
authors.lastname: Krogsgaard-Larsen
authors.forename: F S
authors.initials: FS
authors.lastname: Jørgensen
mesh_terms: D000700:Analgesics / Q000494:pharmacology; D005998:Glycine / Q000037:antagonists & inhibitors*; D007555:Isoxazoles / Q000737:chemistry* / Q000494:pharmacology*; D008958:Models, Molecular; D008968:Molecular Conformation; D018079:Receptors, GABA / Q000187:drug effects*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000700:Analgesics; D007555:Isoxazoles; D018079:Receptors, GABA; C015542:gaboxadol; D005998:Glycine