Allosteric GABAA Receptor Modulators-A Review on the Most Recent Heterocyclic Chemotypes and Their Synthetic Accessibility.

GABAA receptor modulators are structurally almost as diverse as their target protein. A plethora of heterocyclic scaffolds has been described as modulating this extremely important receptor family. Some made it into clinical trials and, even on the market, some were dismissed. This review focuses on the synthetic accessibility and potential for library synthesis of GABAA receptor modulators containing at least one heterocyclic scaffold, which were disclosed within the last 10 years.

Distinct approaches to language pathway tractography: comparison of anatomy-based, repetitive navigated transcranial magnetic stimulation (rTMS)-based, and rTMS-enhanced diffusion tensor imaging-fiber tracking.

OBJECTIVE: Visualization of subcortical language pathways by means of diffusion tensor imaging-fiber tracking (DTI-FT) is evolving as an important tool for surgical planning and decision making in patients with language-suspect brain tumors. Repetitive navigated transcranial magnetic stimulation (rTMS) cortical language mapping noninvasively provides additional functional information. Efforts to incorporate rTMS data into DTI-FT are promising, but the lack of established protocols makes it hard to assess clinical utility. The authors performed DTI-FT of important language pathways by using five distinct approaches in an effort to evaluate the respective clinical usefulness of each approach. METHODS: Thirty patients with left-hemispheric perisylvian lesions underwent preoperative rTMS language mapping and DTI. FT of the principal language tracts was conducted according to different strategies: Ia, anatomical landmark based; Ib, lesion-focused landmark based; IIa, rTMS based; IIb, rTMS based with postprocessing; and III, rTMS enhanced (based on a combination of structural and functional data). The authors analyzed the respective success of each method in revealing streamlines and conducted a multinational survey with expert clinicians to evaluate aspects of clinical utility. RESULTS: The authors observed high usefulness and accuracy ratings for anatomy-based approaches (Ia and Ib). Postprocessing of rTMS-based tractograms (IIb) led to more balanced perceived information content but did not improve the usefulness for surgical planning and risk assessment. Landmark-based tractography (Ia and Ib) was most successful in delineating major language tracts (98% success), whereas rTMS-based tractography (IIa and IIb) frequently failed to reveal streamlines and provided less complete tractograms than the landmark-based approach (p < 0.001). The lesion-focused landmark-based (Ib) and the rTMS-enhanced (III) approaches were the most preferred methods. CONCLUSIONS: The lesion-focused landmark-based approach (Ib) achieved the best ratings and enabled visualization of the principal language tracts in almost all cases. The rTMS-enhanced approach (III) was positively evaluated by the experts because it can reveal cortico-subcortical connections, but the functional relevance of these connections is still unclear. The use of regions of interest derived solely from cortical rTMS mapping (IIa and IIb) leads to cluttered images that are of limited use in clinical practice.

Tricyclic antipsychotics and antidepressants can inhibit α5-containing GABAA receptors by two distinct mechanisms.

BACKGROUND AND PURPOSE: Many psychotherapeutic drugs, including clozapine, display polypharmacology and act on GABAA receptors. Patients with schizophrenia show alterations in function, structure and molecular composition of the hippocampus, and a recent study demonstrated aberrant levels of hippocampal α5 subunit-containing GABAA receptors. The purpose of this study is to investigate the effects of tricyclic compounds on α5 subunit-containing receptor subtypes. EXPERIMENTAL APPROACH: Functional studies of effects by seven antipsychotic and antidepressant medications were performed in several GABAA receptor subtypes by two-electrode voltage-clamp electrophysiology using Xenopus laevis oocytes. Computational structural analysis was employed to design mutated constructs of the α5 subunit, probing a novel binding site. Radioligand displacement data complemented the functional and mutational findings. KEY RESULTS: The antipsychotic drugs clozapine and chlorpromazine exerted functional inhibition on multiple GABAA receptor subtypes, including those containing α5-subunits. Based on a chlorpromazine binding site observed in a GABA-gated bacterial homologue, we identified a novel site in α5 GABAA receptor subunits and demonstrate differential usage of this and the orthosteric sites by these ligands. CONCLUSION AND IMPLICATIONS: Despite high molecular and functional similarities among the tested ligands, they reduce GABA currents by differential usage of allosteric and orthosteric sites. The chlorpromazine site we describe here is a new potential target for optimizing antipsychotic medications with beneficial polypharmacology. Further studies in defined subtypes are needed to substantiate mechanistic links between the therapeutic effects of clozapine and its action on certain GABAA receptor subtypes.