Synthesis of chiral GABAA receptor subtype selective ligands as potential agents to treat schizophrenia as well as depression

Li, Guanguan; Rajesh, Stephen Michael; Kodali, Revathi; Zahn, Nicolas M; Tiruveedhula, V. V. N. Phani Babu; Huber, Alec; Schussman, Melissa K.; Qualmann, Krista J.; Panhans, Cristina M; Raddatz, Nicholas J.; Baker, David A.; Prevot, Thomas D.; Banasr, Mounira; Sibille, Etienne; Arnold, Leggy A.; Cook, James M.

doi:10.24820/ark.5550190.p010.460

Cited by 15 publications

(16 citation statements)

References 44 publications

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“…Amides are commonly used as replacements to improve metabolic stability and bioavailability [31]. Hence, a series of amide IBZD ligands were designed [32] that fit the pharmacophore/receptor model [27], with similar or increased preferential binding affinity and efficacy at GABAA-Rs, compared to corresponding esters [33]. All four amide ligands, referred herein as GL-II-73, GL-II-74, GL-II-75, and GL-II-76, were prepared from the SH-053-2’F-R-CH3 parent compound following steps described in the online supplementary Methods and online supplementary Figure S1.…”

Section: Methodsmentioning

confidence: 99%

Novel Benzodiazepine-Like Ligands with Various Anxiolytic, Antidepressant, or Pro-Cognitive Profiles

Prevot¹,

Vidojević

et al. 2019

Complex Psychiatry

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124

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Altered gamma-aminobutyric acid (GABA) function is consistently reported in psychiatric disorders, normal aging, and neurodegenerative disorders and reduced function of GABA interneurons is associated with both mood and cognitive symptoms. Benzodiazepines (BZ) have broad anxiolytic, but also sedative, anticonvulsant and amnesic effects, due to nonspecific GABA-A receptor (GABAA-R) targeting. Varying the profile of activity of BZs at GABAA-Rs is predicted to uncover additional therapeutic potential. We synthesized four novel imidazobenzodiazepine (IBZD) amide ligands and tested them for positive allosteric modulation at multiple α-GABAA-R (α-positive allosteric modulators), pharmacokinetic properties, as well as anxiolytic and antidepressant activities in adult mice. Efficacy at reversing stress-induced or age-related working memory deficits was assessed using a spontaneous alternation task. Diazepam (DZP) was used as a control. Three ligands (GL-II-73, GL-II-74, and GL-II-75) demonstrated adequate brain penetration and showed predictive anxiolytic and antidepressant efficacies. GL-II-73 and GL-II-75 significantly reversed stress-induced and age-related working memory deficits. In contrast, DZP displayed anxiolytic but no antidepressant effects or effects on working memory. We demonstrate distinct profiles of anxiolytic, antidepressant, and/or pro-cognitive activities of newly designed IBZD amide ligands, suggesting novel therapeutic potential for IBZD derivatives in depression and aging.

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Section: Methodsmentioning

confidence: 99%

Novel Benzodiazepine-Like Ligands with Various Anxiolytic, Antidepressant, or Pro-Cognitive Profiles

Prevot¹,

Vidojević

et al. 2019

Complex Psychiatry

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124

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“…The synthesis of the majority of ligands in Table 1 , Table 2 and Table 4 has been described in Li et al [ 39 , 40 ] The synthesis of imidazodiazepine oxadiazoles ( Table 3 ) has been described in Cook et al [ 41 , 42 ].…”

Section: Methodsmentioning

confidence: 99%

A Structure-Activity Relationship Comparison of Imidazodiazepines Binding at Kappa, Mu, and Delta Opioid Receptors and the GABAA Receptor

Nieman

Mian

et al. 2020

Molecules

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Analgesic and anti-inflammatory properties mediated by the κ opioid receptor (KOR) have been reported for oxadiazole imidazodiazepines. Affinities determined by radioligand competition assays of more than seventy imidazodiazepines using cell homogenates from HEK293 cells that overexpress KOR, µ opioid receptor (MOR), and δ opioid receptor (DOR) are presented. Affinities to synaptic, benzodiazepine-sensitive receptors (BZR) were determined with rat brain extract. The highest affinity for KOR was recorded for GL-I-30 (Ki of 27 nM) and G-protein recruitment was observed with an EC50 of 32 nM. Affinities for MOR and DOR were weak for all compounds. Ester and amide imidazodiazepines were among the most active KOR ligands but also competed with 3H-flunitrazepam for brain extract binding, which is mediated predominately by gamma aminobutyric acid type A receptors (GABAAR) of the α1-3β2-3γ1-2 subtypes. Imidazodiazepines with carboxylic acid and primary amide groups did not bind KOR but interacted strongly with GABAARs. Pyridine substitution reduced KOR affinity. Oxadiazole imidazodiazepines exhibited good KOR binding and interacted weakly with BZR, whereas oxazole imidazodiazepines were more selective towards BZR. Compounds that lack the imidazole moiety, the pendent phenyl, or pyridine substitutions exhibited insignificant KOR affinities. It can be concluded that a subset of imidazodiazepines represents novel KOR ligands with high selectivity among opioid receptors.

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“…The rotarod experiment was performed according to the previously published protocol. 25 In addition, LKG-I-70 (6) was assayed on the rotarod and no sign of sedation nor ataxia was observed even up to 100 mg/kg. There was also no loss of righting response.…”

Section: Rotarod Studymentioning

confidence: 99%

Design, synthesis and characterization of novel gamma‑aminobutyric acid type A receptor ligands

Pandey¹,

Khan²,

Golani³

et al. 2020

Arkivoc

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Synthesis of chiral GABAA receptor subtype selective ligands as potential agents to treat schizophrenia as well as depression

Cited by 15 publications

References 44 publications

Novel Benzodiazepine-Like Ligands with Various Anxiolytic, Antidepressant, or Pro-Cognitive Profiles

Novel Benzodiazepine-Like Ligands with Various Anxiolytic, Antidepressant, or Pro-Cognitive Profiles

A Structure-Activity Relationship Comparison of Imidazodiazepines Binding at Kappa, Mu, and Delta Opioid Receptors and the GABAA Receptor

Design, synthesis and characterization of novel gamma‑aminobutyric acid type A receptor ligands

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