title: Evaluation and synthesis of aminohydroxyisoxazoles and pyrazoles as potential glycine agonists.
abstract: Except for structurally similar small amino acids, such as alanine, beta-alanine, and serine, compounds acting as glycine-receptor agonists are an unknown class of pharmacological agents. To investigate the potential of small, substituted heterocycles to act as glycine agonists, we have evaluated the similarities between glycine and a series of hydroxy- and amino-substituted pyrazoles and isoxazoles through complementary molecular modeling techniques. Using a "scorecard approach" to determine the overall similarity of projected agonist structures to glycine, we prioritized synthesis and subsequently prepared several novel derivatives. The biological activity of these compounds was compared to that of glycine by using a [3H]strychnine-mediated glycine receptor binding assay. Despite the close similarity in the calculated parameters when compared to glycine, no significant receptor-binding activity was observed for the targeted analogues. These results illustrate the structurally exacting nature of the glycine receptor.
authors.affiliation: Department of Chemistry, Warner-Lambert Company, Ann Arbor, Michigan 48105.
authors.forename: J
authors.initials: J
authors.lastname: Drummond
authors.forename: G
authors.initials: G
authors.lastname: Johnson
authors.forename: D G
authors.initials: DG
authors.lastname: Nickell
authors.forename: D F
authors.initials: DF
authors.lastname: Ortwine
authors.forename: R F
authors.initials: RF
authors.lastname: Bruns
authors.forename: B
authors.initials: B
authors.lastname: Welbaum
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D055598:Chemical Phenomena; D002621:Chemistry; D003902:Detergents; D005998:Glycine / Q000378:metabolism* / Q000494:pharmacology; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D008958:Models, Molecular; D010080:Oxazoles / Q000138:chemical synthesis*; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D000644:Quaternary Ammonium Compounds; D051381:Rats; D018009:Receptors, Glycine; D017981:Receptors, Neurotransmitter / Q000187:drug effects*; D013116:Spinal Cord / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D003902:Detergents; D007555:Isoxazoles; D010080:Oxazoles; D011720:Pyrazoles; D000644:Quaternary Ammonium Compounds; D018009:Receptors, Glycine; D017981:Receptors, Neurotransmitter; D005998:Glycine