ABSTRACT
Isoxazolo[3,4-d] pyridazinones ([3,4-d]s) are selective positive modulators of the metabotropic glutamate receptors (mGluRs) subtypes 2 and 4, with no functional cross reactivity at mGluR1a, mGLuR5 or mGluR8. Modest binding for two of the [3,4-d]s is observed at the allosteric fenobam mGluR5 site, but not sufficient to translate into a functional effect. The structure activity relationship (SAR) for mGluR2 and mGluR4 are distinct: the compounds which select for mGluR2 all contain fluorine on the N-6 aryl group. Furthermore, the [3,4-d]s in this study showed no significant binding at inhibitory GABAA, nor excitatory NMDA receptors, and previously we had disclosed that they lack significant activity at the System Xc-Antiporter. A homology model based on Conn's mGluR1 crystal structure was examined, and suggested explanations for a preference for allosteric over orthosteric binding, subtype selectivity, and suggested avenues for optimization of efficacy as a reasonable working hypothesis.
Subject(s)
Isoxazoles/chemistry , Pyridazines/chemistry , Pyridazines/pharmacology , Receptors, Metabotropic Glutamate/drug effects , Allosteric Regulation , Animals , Receptors, Metabotropic Glutamate/chemistry , Structure-Activity RelationshipABSTRACT
Microwave accelerated reaction system (MARS) technology provided a good method to obtain selective and open isoxazole ligands that bind to and inhibit the Sxc- antiporter. The MARS provided numerous advantages, including: shorter time, better yield and higher purity of the product. Of the newly synthesized series of isoxazoles the salicyl hydrazide 6 exhibited the highest level of inhibitory activity in the transport assay. A homology model has been developed to summarize the SAR results to date, and provide a working hypothesis for future studies.
Subject(s)
Amino Acid Transport System y+/antagonists & inhibitors , Isoxazoles/chemistry , Isoxazoles/pharmacology , Amino Acid Transport System y+/chemistry , Amino Acid Transport System y+/metabolism , Cell Line , Cystine/metabolism , Glutamic Acid/metabolism , Humans , Isoxazoles/chemical synthesis , Microwaves , Molecular Docking Simulation , Structural Homology, ProteinABSTRACT
In the title compound, C27H23N3O2, the geminal benzyl groups branching out from the methine adjacent to the isoxazole group are both syn-oriented to the methyl group of the pyridazinone moiety, as reflected by C-C distances of 3.812â (2) and 4.369â (2)â Å between the methyl carbon and the nearest ring carbon of each benzyl group. This kind of conformation is retained in CDCl3 solution, as evidenced by distinct phenyl-shielding effects on the (1)H NMR signals of the methyl H atoms. The isoxazolo[3,4-d]pyridazin ring system is virtually planar (r.m.s. deviation from planarity = 0.031â Å), but the N-bonded phenyl group is inclined to the former by an ring-ring angle of 55.05â (3)°. In the crystal, the T-shaped mol-ecules are arranged in an inter-locked fashion, forming rod-like assemblies along [10-1]. The mol-ecules are held together by unremarkable weak C-Hâ¯N, C-Hâ¯O and C-Hâ¯π inter-actions (C-O,N,C > 3.4â A), while significant π-π-stacking inter-actions are absent.