Imidazobenzodiazepines

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James M Cook - One of the best experts on this subject based on the ideXlab platform.

  • The Effects of pH on the Structure and Bioavailability of Imidazobenzodiazepine-3-Carboxylate MIDD0301.
    Molecular Pharmaceutics, 2020
    Co-Authors: M. S. Rashid Roni, James M Cook, Nicolas M Zahn, Guanguan Li, Yeunus Mian, Brandon N. Mikulsky, Daniel E. Knutson, Douglas C. Stafford, Leggy A. Arnold
    Abstract:

    We describe the effects of pH on the structure and bioavailability of MIDD0301, an oral lead compound for asthma. MIDD0301 interacts with peripheral GABAA receptors to reduce lung inflammation and airway smooth muscle constriction. The structure of MIDD0301 combines basic imidazole and carboxylic acid function in the same diazepine scaffold, resulting in high solubility at neutral pH. Furthermore, we demonstrated that MIDD0301 can interconvert between a seven-membered ring structure at neutral pH and an acyclic compound at or below pH 3. Both structures have two stable conformers in solution that can be observed by 1H NMR at room temperature. Kinetic analysis showed opening and closing of the seven-membered ring of MIDD0301 at gastric and intestinal pH, occurring with different rate constants. However, in vivo studies showed that the interconversion kinetics are fast enough to yield similar MIDD0301 blood and lung concentrations for neutral and acidic formulations. Importantly, acidic and neutral formulations of MIDD0301 exhibit high lung distribution with low concentrations in brain. These findings demonstrate that MIDD0301 interconverts between stable structures at neutral and acidic pH without changes in bioavailability, further supporting its formulation as an oral asthma medication.

  • Non-sedating benzodiazepines cause contractile paralysis and tissue damage in the parasitic blood fluke Schistosoma mansoni
    bioRxiv, 2019
    Co-Authors: Paul Mccusker, James M Cook, Guanguan Li, Yeunus Mian, V. V. N. Phani Babu Tiruveedhula, Farjana Rashid, Lalit K. Golani, Brian C. Smith, John D. Chan
    Abstract:

    Abstract Parasitic flatworm infections (e.g. tapeworms and fluke worms) are treated by a limited number of drugs. In most cases, control is reliant upon praziquantel (PZQ) monotherapy. However, PZQ is ineffective against sexually immature parasites, and there have also been several concerning reports of cestode and trematode infections with poor PZQ cure-rates, emphasizing the need for alternative therapies to treat these infections. We have revisited a series of benzodiazepines, given the known anti-schistosomal activity of meclonazepam (MCLZ). MCLZ was discovered in the 1970’s but was not brought to market due to dose-limiting sedative side effects. However, in the decades since there have been advances in our understanding of the benzodiazepine GABAA receptor sub-types that drive sedation and the development of sub-type selective, non-sedating ligands. Additionally, the sequencing of flatworm genomes reveals that parasitic trematodes and cestodes have lost GABAAR-like ligand gated anion channels, indicating that MCLZ’s anti-parasitic target is likely distinct from the human receptors that drive sedation. Therefore, we screened a library of classical and non-sedating 1,4-benzodiazepines against Schistosoma mansoni and identified a series of Imidazobenzodiazepines that immobilize worms in vitro. One of these hits, Xhe-II-048 also disrupted the parasite tegument, causing extensive vacuole formation beneath the apical membrane. The imidazobenzodiazepine compound series identified has a dramatically lower (∼1 log) affinity for human central benzodiazepine binding site and is a promising starting point for the development of novel anti-schistosomal benzodiazepines with minimal host side-effects. Author Summary Over 200 million people are infected with schistosomiasis, yet there are limited therapeutic options available to treat this disease. The benzodiazepine meclonazepam is known to cure both intestinal and urinary schistosomiasis in animal and human studies, but dose-limiting sedation has been a barrier to its development. Little is known about the structure-activity relationship of meclonazepam and other benzodiazepines on schistosomes, or the identity of the parasite receptor for these compounds. However, schistosomes lack obvious homologs to the human GABAARs that cause sedation. This indicates that the parasite target of this drug is distinct from the host receptors that underpin dose-limiting side effects of meclonazepam, and raises the possibility that benzodiazepines with poor GABAAR affinity may still retain anti-parasitic effects. Here, we report an in vitro screen of various benzodiazepines against schistosomes, and the identification of hit compounds that are active against worms yet possess reduced affinity for the human GABAARs that cause sedation.

  • Different Benzodiazepines Bind with Distinct Binding Modes to GABAA Receptors
    ACS Chemical Biology, 2018
    Co-Authors: Al-shaimaa A. Elgarf, James M Cook, Guanguan Li, Shengming Huang, David C. B. Siebert, Friederike Steudle, Angelika Draxler, Margot Ernst, Petra Scholze
    Abstract:

    Benzodiazepines are clinically relevant drugs that bind to GABAA neurotransmitter receptors at the α+/γ2– interfaces and thereby enhance GABA-induced chloride ion flux leading to neuronal hyperpolarization. However, the structural basis of benzodiazepine interactions with their high-affinity site at GABAA receptors is controversially debated in the literature, and in silico studies led to discrepant binding mode hypotheses. In this study, computational docking of diazepam into α+/γ2– homology models suggested that a chiral methyl group, which is known to promote preferred binding to α5-containing GABAA receptors (position 3 of the seven-membered diazepine ring), could possibly provide experimental evidence that supports or contradicts the proposed binding modes. Thus, we investigated three pairs of R and S isomers of structurally different chemotypes, namely, diazepam, imidazobenzodiazepine, and triazolam derivatives. We used radioligand displacement studies as well as two-electrode voltage clamp electrop...

  • anxiolytic like effects of 8 acetylene Imidazobenzodiazepines in a rhesus monkey conflict procedure
    Neuropharmacology, 2010
    Co-Authors: Bradford D Fischer, X He, Stephanie C Licata, Rahul V Edwankar, Zhijian Wang, Shengming Huang, Jianming Yu, Hao Zhou, Edward Merle Johnson, James M Cook
    Abstract:

    Abstract Conflict procedures can be used to study the receptor mechanisms underlying the anxiolytic effects of benzodiazepines and other GABAA receptor modulators. In the present study, we first determined the efficacy and binding affinity of the benzodiazepine diazepam and recently synthesized GABAA receptor modulators JY-XHe-053, XHe-II-053, HZ-166, SH-053-2′F-S-CH3 and SH-053-2′F-R-CH3 at GABAA receptors containing α1, α2, α3 and α5 subunits. Results from these studies suggest that each compound displayed lower efficacy at GABAA receptors containing α1 subunits and varying degrees of efficacy and affinity at GABAA receptors containing α2, α3 and α5 subunits. Next, we assessed their anxiolytic effects using a rhesus monkey conflict procedure in which behavior was maintained under a fixed-ratio schedule of food delivery in the absence (non-suppressed responding) and presence (suppressed responding) of response-contingent electric shock. Relatively non-selective compounds, such as diazepam and JY-XHe-053 produced characteristic increases in rates of suppressed responding at low to intermediate doses and decreased the average rates of non-suppressed responding at higher doses. XHe-II-053 and HZ-166 also produced increases in suppressed responding at low to intermediate doses, but were ineffective at decreasing rates of non-suppressed responding, consistent with their relatively low efficacy at GABAA receptors containing α1 and α5 subunits. In contrast, SH-053-2′F-S-CH3 and SH-053-2′F-R-CH3 produced only partial increases in suppressed responding and were ineffective on non-suppressed responding, consistent with their profiles as partial agonists at GABAA receptors containing α2, α3 and α5 subunits. These behavioral effects suggest that the anxiolytic and rate-reducing effects of GABAA receptor positive modulators are dependent on their relative efficacy and affinity at different GABAA receptor subtypes.

  • Differential sensitivity to inverse agonists of GABAA/benzodiazepine receptors in rats with genetic absence-epilepsy
    Epilepsy Research, 2001
    Co-Authors: M Vergnes, James M Cook, A Boehrer, X He, H Greney, M Dontenwill, C Marescaux
    Abstract:

    Abstract A strain of Wistar rats, genetic absence epilepsy rats from Strasbourg (GAERS), was selected and inbred over 40 generations for occurrence of spontaneous spike-wave discharges characteristic of absence seizures, simultaneously with a strain of non-epileptic rats (NER). GAERS demonstrate an excessive sensitivity to antagonists of the GABA A receptor. The sensitivity to convulsions induced by various inverse agonists of the GABA A /benzodiazepine receptor was compared in GAERS and NERs. The β-carbolines FG 7142 and DMCM, and the Imidazobenzodiazepines RO 19-4603 and the alpha 5-selective RY 024 were several times more convulsant in GAERS than in NERs. The largest differences were found with the non-selective RO 19-4603- and FG 7142. The proconvulsant imidazobenzodiazepine RO 15-4513, binding also to diazepam-insensitive receptors, had low efficacy. The high affinity binding of GABA A /BZD receptors with (3H) RO 15-1788 in the brain of naive rats and after administration of FG 7142 did not differ in GAERS and NERs. The data indicate that the hypersensitivity of GAERS to various inverse agonists of the GABA A /benzodiazepine receptor involves cortical GABA A receptors and is not related to differential activity of a subunit-selective receptor.

Surisetti Suresh - One of the best experts on this subject based on the ideXlab platform.

Phil Skolnick - One of the best experts on this subject based on the ideXlab platform.

  • The imidazobenzodiazepine Ro 15-4513 antagonizes methoxyflurane anesthesia.
    Life Sciences, 2002
    Co-Authors: Eric J. Moody, Phil Skolnick
    Abstract:

    Abstract Parenteral administration of the imidazobenzodiazepine Ro 15-4513 (a high affinity ligand of the benzodiazepine receptor with partial inverse agonist qualities) produced a dose dependent reduction in sleep time of mice exposed to the inhalation anesthetic, methoxyflurane. The reductions in methoxyflurane sleep time ranged from ∼ 20% at 4 mg/kg to ∼ 38% at 32 mg/kg of Ro 15-4513. Co-administration of the benzodiazepine receptor antagonist Ro 15-1788 (16 mg/kg) or the inverse agonists DMCM (5–20 mg/kg) and FG 7142 (22.5 mg/kg) blocks this effect which suggests that the reductions in methoxyflurane sleep time produced by Ro 15-4513 are mediated via occupation of benzodiazepine receptors. Moreover, neither DMCM (5–20 mg/kg) nor FG 7142 (22.5 mg/kg) reduced methoxyflurane sleep time which suggests this effect of Ro 15-4513 cannot be attributed solely to its partial inverse agonist properties. These observations support recent findings that inhalation anesthetics may produce their depressant effects via perturbation of the benzodiazepine/GABA receptor chloride channel complex, and suggest that Ro 15-4513 may serve as a prototype of agents capable of antagonizing the depressant effects of inhalation anesthetics such as methoxyflurane.

  • Pharmacological properties of recombinant "diazepam-insensitive" GABAA receptors.
    Neuropharmacology, 2000
    Co-Authors: D. Gunnersen, C.m. Kaufman, Phil Skolnick
    Abstract:

    Abstract Both native and recombinant “diazepam-insensitive” GABAA receptors (DI) are characterized by the very low affinities of prototypic 1,4-benzodiazepines such as diazepam and the high affinity of an imidazobenzodiazepine, Ro 15-4513. The presence of either an α4 or α6 subunit imparts this unusual pharmacological profile to DI. Based on the affinities of these compounds at recombinant DI, the pharmacological properties of α4- and α6-bearing receptor isoforms appear to be very similar if not identical. Using a larger sample of structurally diverse compounds, we now demonstrate distinct but related ligand binding profiles of recombinant α4β2γ2 and α6β2γ2 DI. Comparison of 18 ligands drawn from three principal structural groups (β-carbolines, Imidazobenzodiazepines and pyrazoloquinolinones) revealed that the affinity of at least one representative from each group differed by >5-fold between α4- and α6β2γ2 receptors. While the high correlation (r2 = 0.926; p

  • synthesis and pharmacological properties of novel 8 substituted Imidazobenzodiazepines high affinity selective probes for alpha 5 containing gabaa receptors
    Journal of Medicinal Chemistry, 1996
    Co-Authors: Rona J Hu, Phil Skolnick, Puwen Zhang, James M Cook
    Abstract:

    The synthesis and pharmacological properties of Imidazobenzodiazepines with both high affinity and selectivity for α5-containing GABAA receptors are described. Four of these compounds (5, 6, 8, and 9) inhibited [3H]flunitrazepam binding to recombinant α5β2γ2 GABAA receptors with IC50 values between ∼0.4 and 5 nM. These compounds were ≥24−75-fold more selective for recombinant receptors containing α5 subunits compared to other, “diazepam-sensitive” GABAA receptors containing either α1, α2, or α3 subunits. Imidazobenzodiazepine 9 (used as the prototypical α5 selective ligand) inhibited [3H]flunitrazepam binding to hippocampal membranes with high- and low-affinity components (IC50 0.6 ± 0.2 and 85.6 ± 13.1 nM, respectively), representing ∼16% and ∼84% of the receptor pool. Inhibition of [3H]flunitrazepam binding to cerebellar membranes with imidazobenzodiazepine 9 was best fitted to a single population of sites with an IC50 of 79.8 ± 18.3 nM. These Imidazobenzodiazepines behaved as GABA negative ligands in r...

  • contribution of diazepam insensitive gabaa receptors to the alcohol antagonist properties of ro 15 4513 and related Imidazobenzodiazepines
    Pharmacology Biochemistry and Behavior, 1995
    Co-Authors: Bradford D Harris, Eric J. Moody, Ziqiang Gu, Phil Skolnick
    Abstract:

    Both in vivo and in vitro studies have shown that Ro 15–4513 can antagonize many of the pharmacologic actions of ethanol. In contrast to many benzodiazepine receptor (BzR) ligands, Ro 15–4513 binds with high affinity to a novel GABAA receptor subtype, referred to as “diazepam-insensitive” (DI). This study examined the contribution of DI GABAA receptors to the modulation of ethanol-induced sleep time by Ro 15–4513 and related Imidazobenzodiazepines [e.g., Ro 19–4603, Ro16–6028, and ZG-63 (t-butyl-8-chloro-5,6-dihydro-5-methyl-6-oxo-imidazo[1,5,a] [1,4] benzodiazepine-3-carboxylate)] that possess high affinities for this GABAA receptor subtype. Ro 15–4513 (0.6–5 mg/kg) significantly reduced ethanol (3.5 g/kg, IP) sleep time in mice (p < 0.001, analysis of variance). This effect was not blocked by BzR antagonists ZK 93426 (5 mg/kg) and Ro 14-7437 (5 mg/kg), which possess low affinities for DI but bind with high affinities to other “diazepam-sensitive” (DS) GABAA receptor isoforms. Although Ro 19–4603 (2.5 mg/kg) also reduced ethanol sleep time (p < 0.01), this effect was attenuated by coadministration of ZK 93426 (2.5 mg/kg). Ro 16-6028 (2.5 mg/kg) prolonged (p < 0.01) ethanol sleep time. However, in the presence of either Ro 14-7437 (5 mg/kg) or ZK 93426 (2.5 mg/kg) ethanol-induced sleep time was reduced to values approaching those obtained with ethanol in the presence of Ro 15–4513. A low dose (2.5 mg/ kg) of ZG-63 did not significantly affect alcohol sleep time. However, in the presence of ZK 93426, ZG-63 increased sleep time (p < 0.01). In contrast, a higher dose of ZG-63 (7.5 mg/kg) prolonged sleep time, an effect that was attenuated by either ZK 93426 or Ro 14-7437. These findings indicate that although antagonism of ethanol-induced sleep time by Ro 15–4513 is mediated, at least in part, through DI, the contribution of this GABAA receptor isoform to the modulation of ethanol-induced sleep time by structurally related Imidazobenzodiazepines is more variable. The synthesis of compounds with higher selectivity and a range of intrinsic efficacies at DI GABAA receptors is required to better define the role of this receptor isoform in ethanol-induced sleep time.

  • synthesis of novel Imidazobenzodiazepines as probes of the pharmacophore for diazepam insensitive gabaa receptors
    Journal of Medicinal Chemistry, 1995
    Co-Authors: Puwen Zhang, Phil Skolnick, Weijiang Zhang, Bradford D Harris, James M Cook
    Abstract:

    The syntheses of a series of novel Imidazobenzodiazepines and their affinities for diazepam sensitive (DS) and diazepam insensitive (DI) GABA A receptors are described. Imidazobenzodiazepines belong to one of the very few chemical families which exhibit high to moderate potency for DI GABA A receptors. Although Imidazobenzodiazepines such as Ro 15-4513, 20, are the most potent DI GABA A receptor ligands described to date, their selectivity for DI versus DS GABA A receptors is only marginal. Previous structure-activity relationship (SAR) studies of Imidazobenzodiazepines have indicated that the 3- and 8-positions are critical for high-affinity binding to DI GABA A receptors (J. Med. Chem. 1993, 36, 479-490. J. Med. Chem. 1993, 36, 1001-1006. J. Med. Chem. 1993, 36, 1820-1830). In order to determine why the ester function is critical to high affinity at the DI site, we have synthesized several derivatives which have substituents other than an ester at the C(3) position including 3-alkyl-, 3-alkylketo-, 3-alkyl ether, and 3-dialkylamino-substituted Imidazobenzodiazepines. The SAR analysis of these compounds when combined with that of several pyrazoloquinolinones indicates that interactions at H1 and L1 as well as interactions at H2 anti to the imidazole N(2) and at a lipophilic pocket (labeled LDi) about the 3-position are required in order for Imidazobenzodiazepines to exhibit selectivity and high affinity for DI GABA A receptors. Furthermore, the Imidazobenzodiazepines substituted with an electron-donating group (alkoxy function) at position 8 revealed that the change of the substituent at C(8) from an electron-withdrawing to a donating function did not substantially alter either ligand affinity or selectivity for DI GABA A receptors. Thus, a pharmacophore is proposed for DI GABA A receptor ligands, which is characterized by the requirement of a lipophilic pocket LDi about the C(3) position of Imidazobenzodiazepines. Using this model, two pyrazoloquinolinone derivatives were designed and synthesized. Their affinities and selectivities for DI GABA A receptors are consistent with those predicted by the DI GABA A receptor pharmacophore. In addition, examination of the in vitro binding data of 3-alkyl ether analogs confirms that the anti conformation of the ester group at the C(3) position of Imidazobenzodiazepines (Ro15-4513, 20 series) is preferred at both DI and DS GABA A receptors. This constitutes the first evidence (other than molecular modeling) to support the auxillary involvement of H2 at the DI site and is important with regard to the synthesis of other DI GABA A receptor selective ligands in the future. Comparison of the included volume developed here for the DI site vs the included volume for the DS site clearly demonstrates that the DI site is a smaller (subsite) binding cleft than the DS site and is clearly devoid of most of lipophilic area L3 (Figure 6b)

Ruqin Yu - One of the best experts on this subject based on the ideXlab platform.

  • quantitative structure activity relationship studies for the binding affinities of Imidazobenzodiazepines for the α6 benzodiazepine receptor isoform utilizing optimized blockwise variable combination by particle swarm optimization for partial least s
    Qsar & Combinatorial Science, 2007
    Co-Authors: Leqian Hu, Hailong Wu, Jianhui Jiang, Ruqin Yu
    Abstract:

    Binding affinities of a series of substituted Imidazobenzodiazepines for the a6 Benzodiazepine Receptor (BzR) isoform are investigated by the Optimized Blockwise Variable Combination (OBVC) by Particle Swarm Optimization (PSO) based on Partial Least Squares (PLS) modeling. The QSAR analysis result showed that MolRef, AlogP, MR CM**-3 , Rotatable bonds (Rotlbonds), Hydrogen Bond Acceptors (Hbond acceptor), five Jurs descriptors, two Shadow indices descriptors and principal moment of inertia are the most important descriptors among all the investigated descriptors. One can change the molar refractivity, the polar interactions between molecules, the shape of the molecules, the principal moments of inertia about the principal axes of a molecule, the hydrophobic character of the molecule, the number of Rotlbonds and Hbond acceptors of the compounds to adjust the binding affinities of imidazobenzodiazepine for the a6 BzR isoform. The Quantitative Structure-Activity Relationship (QSAR) analysis result was also compared with MLR, PLS, and hierarchical PLS algorithms. It has been demonstrated that OBVC by PSO for PLS modeling shows satisfactory performance in the QSAR analysis.

  • Quantitative Structure–Activity Relationship Studies for the Binding Affinities of Imidazobenzodiazepines for the α6 Benzodiazepine Receptor Isoform Utilizing Optimized Blockwise Variable Combination by Particle Swarm Optimization for Partial Least S
    Qsar & Combinatorial Science, 2006
    Co-Authors: Leqian Hu, Hailong Wu, Jianhui Jiang, Ruqin Yu
    Abstract:

    Binding affinities of a series of substituted Imidazobenzodiazepines for the a6 Benzodiazepine Receptor (BzR) isoform are investigated by the Optimized Blockwise Variable Combination (OBVC) by Particle Swarm Optimization (PSO) based on Partial Least Squares (PLS) modeling. The QSAR analysis result showed that MolRef, AlogP, MR CM**-3 , Rotatable bonds (Rotlbonds), Hydrogen Bond Acceptors (Hbond acceptor), five Jurs descriptors, two Shadow indices descriptors and principal moment of inertia are the most important descriptors among all the investigated descriptors. One can change the molar refractivity, the polar interactions between molecules, the shape of the molecules, the principal moments of inertia about the principal axes of a molecule, the hydrophobic character of the molecule, the number of Rotlbonds and Hbond acceptors of the compounds to adjust the binding affinities of imidazobenzodiazepine for the a6 BzR isoform. The Quantitative Structure-Activity Relationship (QSAR) analysis result was also compared with MLR, PLS, and hierarchical PLS algorithms. It has been demonstrated that OBVC by PSO for PLS modeling shows satisfactory performance in the QSAR analysis.

V Murugesh - One of the best experts on this subject based on the ideXlab platform.