Fenobam

Docking, Molecular Dynamics Simulation and Synthesis of New Fenobam Analogues as mGlu5 Receptor Antagonists.[Pubmed:27585831]

Comb Chem High Throughput Screen. 2016;19(9):764-770.

BACKGROUND: Fenobam is a non-competitive mGluR5 antagonist as an anxiolytic agent. OBJECTIVE: In this research a new series of Fenobam analogues containing thiazole moiety instead of imidazole ring were designed and synthesized. METHODS: The ureido-substituted products were synthesized from reaction of amino thiazole derivatives and isocyanate derivatives in dichloromethane solvent under microwave and ultrasonic irradiation condition. The synthesized compounds structures were established by means of IR, 1HNMR, 13CNMR spectroscopic data. Then, docking calculations were performed on the active site of mGLuR5 and compared to Fenobam as a reference drug by using AutoDock program. The molecular dynamics (MD) simulations were done using GROMACS 5.0.5. RESULTS: Docking studies suggested that all of the compounds possess better binding energy when compared to Fenobam. The results of MD simulations might offer the binding mode of ligand (3b), accuracy of docking and the reliability of active conformations which obtained by AutoDock. CONCLUSION: New derivatives of Fenobam were designed and synthesized that have the better insilico results compared to Fenobam and will evaluate in future studies.

Fmr1 KO and fenobam treatment differentially impact distinct synapse populations of mouse neocortex.[Pubmed:25521380]

Neuron. 2014 Dec 17;84(6):1273-86.

Cognitive deficits in fragile X syndrome (FXS) are attributed to molecular abnormalities of the brain's vast and heterogeneous synapse populations. Unfortunately, the density of synapses coupled with their molecular heterogeneity presents formidable challenges in understanding the specific contribution of synapse changes in FXS. We demonstrate powerful new methods for the large-scale molecular analysis of individual synapses that allow quantification of numerous specific changes in synapse populations present in the cortex of a mouse model of FXS. Analysis of nearly a million individual synapses reveals distinct, quantitative changes in synaptic proteins distributed across over 6,000 pairwise metrics. Some, but not all, of these synaptic alterations are reversed by treatment with the candidate therapeutic Fenobam, an mGluR5 antagonist. These patterns of widespread, but diverse synaptic protein changes in response to global perturbation suggest that FXS and its treatment must be understood as a networked system at the synapse level.

The mGluR5 antagonist fenobam induces analgesic conditioned place preference in mice with spared nerve injury.[Pubmed:25061818]

PLoS One. 2014 Jul 25;9(7):e103524.

Antagonists of metabotropic glutamate receptors (mGluRs) have the potential to act as analgesic drugs that may help alleviate chronic pain. This study was done to look at the possible rewarding properties of the mGluR5 antagonist, Fenobam, in a cognitive assay. Analgesic conditioned place preference (aCPP) was used to examine the effects of Fenobam (30 mg/kg) and the prototypical mGluR5 antagonist, MPEP, and these effects were compared to those of a drug with known analgesic properties, morphine (10 mg/kg). In each experiment, one group of mice received spared nerve injury (SNI) surgery to model chronic pain; the other group received a control sham surgery. Both Fenobam and MPEP induced preference in the SNI mice, such that SNI mice spent significantly more time in the mGluR5 antagonist-paired chamber compared to a vehicle-paired chamber. No such preference developed for sham mice. Morphine induced preference in male and female mice in both the SNI and sham groups. The results showed that Fenobam and MPEP likely reduced on-going distress in the SNI mice, causing them to prefer the chamber paired with the drug compared to the vehicle-paired chamber. Since sham animals did not prefer the drug-paired chamber, these data demonstrate that mGluR5 antagonism is non-rewarding in the absence of pain-like injury.

Dose-dependent, saturable occupancy of the metabotropic glutamate subtype 5 receptor by fenobam as measured with [(11) C]ABP688 PET imaging.[Pubmed:25098663]

Synapse. 2014 Dec;68(12):565-573.

Fenobam is a negative allosteric modulator of the metabotropic glutamate receptor subtype 5 (mGluR5) with inverse agonist activity and is expected to contribute to the treatment of neuropsychiatric disorders involving dysfunction of mGluR5 including Fragile X syndrome. This study examined whether [(11) C]ABP688, an antagonist PET radioligand, competes with Fenobam for the same binding site in the nonhuman primate brain and would allow examination of occupancy-plasma concentration relationships in the evaluation of the drug for target disorders in the human brain. Four paired PET studies with [(11) C]ABP688 were performed in baboons at a baseline condition and after intravenous treatment with Fenobam at different dose levels (0.3-1.33 mg/kg). Total distribution volume (VT ) and binding potential (BPND ) using the cerebellum as a reference region were obtained by the plasma reference graphical method. Then it was examined whether occupancy follows a dose-dependent, saturating pattern that was predicted by a modified first-order Hill equation in individual regions. Baseline regional VT and BPND values agreed with previously published data. Occupancy showed dose-dependent and saturating patterns in individual regions, reaching >90% occupancy at 1.33 mg/kg dose of Fenobam in the majority of regions. To our knowledge, this is the first use of PET to characterize the mGluR5 therapeutic drug Fenobam. This study demonstrates a proof of principle for determining the in vivo occupancy of Fenobam in primates. The results indicate that [(11) C]ABP688 and PET may be useful for examination of occupancy of mGluR5 by Fenobam, which should prove to be useful for designing future studies and treatment of human disease states. Synapse 68:565-573, 2014. (c) 2014 Wiley Periodicals, Inc.

The metabotropic glutamate receptor subtype 5 antagonist fenobam is analgesic and has improved in vivo selectivity compared with the prototypical antagonist 2-methyl-6-(phenylethynyl)-pyridine.[Pubmed:19515968]

J Pharmacol Exp Ther. 2009 Sep;330(3):834-43.

Metabotropic glutamate receptor subtype 5 (mGlu5) has been demonstrated to play a role in the modulation of numerous nociceptive modalities. When administered via peripheral, intrathecal, or systemic routes, mGlu5 antagonists have analgesic properties in a variety of preclinical pain models. Despite a wealth of data supporting the use of mGlu5 antagonists to treat pain, studies have been limited to preclinical animal models due to a lack of mGlu5 antagonists that are approved for use in humans. It has been demonstrated previously that Fenobam [N-(3-chlorophenyl)-N'-(4,5-dihydro-1-methyl-4-oxo-1H-imidazole-2-yl)urea], an anxiolytic shown to be safe and effective in human trials, is a selective and potent noncompetitive antagonist of mGlu5 (J Pharmacol Exp Ther 315:711-721, 2005). Here, we report a series of studies aimed at testing whether Fenobam, similar to the prototypical mGlu5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP), has analgesic properties in mice. We show that Fenobam reduces formalin-induced pain behaviors and relieves established inflammation-induced thermal hypersensitivity in mice. Similar results were seen with MPEP. Administration of Fenobam resulted in an increase in locomotor activity in the open-field task but did not impair performance on the accelerating Rotarod. Analysis of brain and plasma Fenobam levels indicated that Fenobam is rapidly concentrated in brain after intraperitoneal administration in mice but is essentially cleared from circulation within 1 h after injection. Fenobam had no analgesic effect in mGlu5 knockout mice, whereas the prototypical antagonist MPEP retained significant analgesic efficacy in mGlu5 knockouts. These results demonstrate that Fenobam is analgesic in mice and has an improved in vivo selectivity for mGlu5 over MPEP.

Fenobam: a clinically validated nonbenzodiazepine anxiolytic is a potent, selective, and noncompetitive mGlu5 receptor antagonist with inverse agonist activity.[Pubmed:16040814]

J Pharmacol Exp Ther. 2005 Nov;315(2):711-21.

Fenobam [N-(3-chlorophenyl)-N'-(4,5-dihydro-1-methyl-4-oxo-1H-imidazole-2-yl)urea] is an atypical anxiolytic agent with unknown molecular target that has previously been demonstrated both in rodents and human to exert anxiolytic activity. Here, we report that Fenobam is a selective and potent metabotropic glutamate (mGlu)5 receptor antagonist acting at an allosteric modulatory site shared with 2-methyl-6-phenylethynyl-pyridine (MPEP), the protypical selective mGlu5 receptor antagonist. Fenobam inhibited quisqualate-evoked intracellular calcium response mediated by human mGlu5 receptor with IC(50) = 58 +/- 2 nM. It acted in a noncompetitive manner, similar to MPEP and demonstrated inverse agonist properties, blocking 66% of the mGlu5 receptor basal activity (in an over expressed cell line) with an IC(50) = 84 +/- 13 nM. [(3)H]Fenobam bound to rat and human recombinant receptors with K(d) values of 54 +/- 6 and 31 +/- 4 nM, respectively. MPEP inhibited [(3)H]Fenobam binding to human mGlu5 receptors with a K(i) value of 6.7 +/- 0.7 nM, indicating a common binding site shared by both allosteric antagonists. Fenobam exhibits anxiolytic activity in the stress-induced hyperthermia model, Vogel conflict test, Geller-Seifter conflict test, and conditioned emotional response with a minimum effective dose of 10 to 30 mg/kg p.o. Furthermore, Fenobam is devoid of GABAergic activity, confirming previous reports that Fenobam acts by a mechanism distinct from benzodiazepines. The non-GABAergic activity of Fenobam, coupled with its robust anxiolytic activity and reported efficacy in human in a double blind placebo-controlled trial, supports the potential of developing mGlu5 receptor antagonists with an improved therapeutic window over benzodiazepines as novel anxiolytic agents.

Fenobam is a selective, orally active, and non-competitive mGluR5 antagonist acting at an allosteric modulatory site (Kd values are 54 and 31 nM for rat and human recombinant mGlu5 receptors, respectively). Fenobam displays inverse agonist activity which blocks the mGlu5 receptor basal activity with an IC50 of 84 nM. Fenobam exerts anxiolytic activity.

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