While monoaminergic deficits are evident in all depressed patients, nonresponders are characterized by impaired GABA-ergic signaling and the simultaneous presence of the inflammatory component. Pharmacological agents able to curb pathological immune responses and modulate ineffective GABA-ergic neurotransmission are thought to improve therapeutic outcomes in the treatment-resistant subgroup of depressed patients. Here, we report on a set of dually acting molecules designed to simultaneously modulate GABA-A and 5-HT 6 receptor activity. The serotonin 5-HT 6 receptor was chosen as a complementary molecular target, due to its promising antidepressant-like activities reported in animal studies. Within the study we identified that lead molecule 16 showed a desirable receptor profile and physicochemical properties. In pharmacological studies, 16 was able to reduce the secretion of proinflammatory cytokines and decrease oxidative stress markers. In animal studies, 16 exerted antidepressant-like activity deriving from a synergic interplay between 5-HT 6 and GABA-A receptors. Altogether, the presented findings point to hybrid 16 as an interesting tool that interacts with pharmacologically relevant targets, matching the pathological dysfunction of depression associated with neuroinflammation.
Modulation of α1β2γ2GABA-A receptor subpopulation expressed in the basal ganglia region is a conceptually novel mode of pharmacological strategy that offers prospects to tackle a variety of neurological dysfunction. Although clinical findings provided compelling evidence for the validity of this strategy, the current chemical space of molecules able to modulate the α1/γ2 interface of the GABA-A receptor is limited to imidazo[1,2-a]pyridine derivatives that undergo rapid biotransformation. In response to a deficiency in the chemical repertoire of GABA-A receptors, we identified a series of 2-(4-fluorophenyl)-1H-benzo[d]imidazoles as positive allosteric modulators (PAMs) with improved metabolic stability and reduced potential for hepatotoxicity, where lead molecules 9 and 23 displayed interesting features in a preliminary investigation. We further disclose that the identified scaffold shows a preference for interaction with the α1/γ2 interface of the GABA-A receptor, delivering several PAMs of the GABA-A receptor. The present work provides useful chemical templates to further explore the therapeutic potential of GABA-A receptor ligands and enriches the chemical space of molecules suitable for the interaction with the α1/γ2 interface.
Szczęśliwy traf (z ang. serendipity?), oznacza zjawisko zbiegu okoliczności prowadzące do niespodziewanych odkryć, które może być również związane z umiejętnością wyciągania wartościowych wniosków z pozornie nieistotnych wyników. Odkrycie penicyliny G mogłoby nie mieć miejsca, gdyby nie warunki pogodowe w Wielkiej Brytanii w trakcie urlopu Alexandra Fleminga w 1928 roku, podczas gdy benzodiazepiny, jedną z najważniejszych grup leków anksjolitycznych, pośrednio można zawdzięczać wyczerpaniu zapasu czystego szkła w laboratorium Leona Sternbacha. Odkrycie przeciwzakrzepowej warfaryny nie miałoby miejsca, gdyby nie epidemia bydła oraz nieudana próba samobójcza młodego rekruta. Pomyłka w aptecznej dostawie przyczyniła się do późniejszego wprowadzenia do lecznictwa paracetamolu, a błędna teoria wpływu pola elektrycznego na podziały komórkowe zaowocowała stworzeniem przeciwnowotworowych leków alkilujących, takich jak cis-platyna. Niniejsza praca opisuje historię leków, których odkrycie zawdzięcza się przypadkowym zbiegom okoliczności.
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