ABSTRACT
δ-Selective compounds 1 and 2 (DS1, compound 22; DS2, compound 16) were introduced as functionally selective modulators of δ-containing GABA type A receptors (GABAAR). In our hands, [3H]EBOB-binding experiments with recombinant GABAAR and compound 22 showed no proof of δ-selectivity, although there was a minimally higher preference for the α4ß3δ and α6ß2/3δ receptors with respect to potency. In order to delineate the structural determinants of δ preferences, we synthesized 25 derivatives of DS1 and DS2, and investigated their structure-activity relationships (SAR). Four of our derivatives showed selectivity for α6ß3δ receptors (29, 38, 39, and 41). For all of them, the major factors that distinguished them from compound 22 were variations at the para-positions of their benzamide groups. However, two compounds (29 and 39), when tested in the presence of GABA, revealed effects at several additional GABAAR. The newly synthesized compounds will still serve as useful tools to investigate α6ß3δ receptors.
Subject(s)
GABA-A Receptor Antagonists/chemistry , Imidazoles/metabolism , Pyridines/metabolism , Receptors, GABA-A/metabolism , Humans , Imidazoles/chemistry , Imidazoles/pharmacology , Inhibitory Concentration 50 , Protein Subunits/metabolism , Pyridines/chemistry , Pyridines/pharmacology , Structure-Activity RelationshipABSTRACT
The western corn rootworm (WCR; Diabrotica virgifera virgifera LeConte) is a major pest of maize (Zea mays) that is well adapted to most crop management strategies. Breeding for tolerance is a promising alternative to combat WCR but is currently constrained by a lack of physiological understanding and phenotyping tools. We developed dynamic precision phenotyping approaches using 11C with positron emission tomography, root autoradiography, and radiometabolite flux analysis to understand maize tolerance to WCR Our results reveal that WCR attack induces specific patterns of lateral root growth that are associated with a shift in auxin biosynthesis from indole-3-pyruvic acid to indole-3-acetonitrile. WCR attack also increases transport of newly synthesized amino acids to the roots, including the accumulation of Gln. Finally, the regrowth zones of WCR-attacked roots show an increase in Gln turnover, which strongly correlates with the induction of indole-3-acetonitrile-dependent auxin biosynthesis. In summary, our findings identify local changes in the auxin biosynthesis flux network as a promising marker for induced WCR tolerance.
