Discovery of Imidazo[1,2-<i>b</i>][1,2,4]triazines as GABA<sub>A</sub> α2/3 Subtype Selective Agonists for the Treatment of Anxiety

Mg, Russell; Rw, Carling; Lj, Street; Hallett, DJ; Goodacre, Simon; Mezzogori, Elena; Reader, Michael; Sm, Cook; Fa, Bromidge; Newman, Richard J.; Smith, A.D.; Ka, Wafford; Marshall, Garland R.; Ds, Reynolds; Dias, Rebecca; Ferris, Pushpinder; Stanley, John C.; Lincoln, Rachael J.; Sj, Tye; Wf, Sheppard; Sohal, Bindi; Pike, A; Domínguez, María del Carmen; Atack, John; Jl, Castro

doi:10.1021/jm051200u

Cited by 44 publications

(29 citation statements)

References 22 publications

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“…On the other hand, it is noticeable that standard studies of motor activity, which form the very basis of knowledge of drug effects on behavior (Kelley, 1993), were not employed for characterization of recently reported putative anxioselective compounds (Atack et al, 2006c;Jennings et al, 2006;Griebel et al, 2001;Russell et al, 2006). Jennings et al (2006) reported on an a2/a3-BZ site-selective ligand from the class of imidazo[1,2-b][1,2,4]triazines with anxiolytic activity in the rat EPM test at the dose of 1 mg/kg, which showed no motor incapacitation in the mouse rotarod test at doses up to 30 mg/kg.…”

Section: Discussionmentioning

confidence: 99%

Are GABAA Receptors Containing α5 Subunits Contributing to the Sedative Properties of Benzodiazepine Site Agonists?

Savić

Huang

Furtmüller

et al. 2007

Neuropsychopharmacol

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Classical benzodiazepines (BZs) exert anxiolytic, sedative, hypnotic, muscle relaxant, anticonvulsive, and amnesic effects through potentiation of neurotransmission at GABA A receptors containing a 1 , a 2 , a 3 or a 5 subunits. Genetic studies suggest that modulation at the a 1 subunit contributes to much of the adverse effects of BZs, most notably sedation, ataxia, and amnesia. Hence, BZ site ligands functionally inactive at GABA A receptors containing the a 1 subunit are considered to be promising leads for novel, anxioselective anxiolytics devoid of sedative properties. In pursuing this approach, we used two-electrode voltage clamp experiments in Xenopus oocytes expressing recombinant GABA A receptor subtypes to investigate functional selectivity of three newly synthesized BZ site ligands and also compared their in vivo behavioral profiles. The compounds were functionally selective for a 2 -, a 3 -, and a 5 -containing subtypes of GABA A receptors (SH-053-S-CH3 and SH-053-S-CH3-2 0 F) or essentially selective for a 5 subtypes (SH-053-R-CH3). Possible influences on behavioral measures were tested in the elevated plus maze, spontaneous locomotor activity, and rotarod test, which are considered primarily predictive of the anxiolytic, sedative, and ataxic influence of BZs, respectively. The results confirmed the substantially diminished ataxic potential of BZ site agonists devoid of a 1 subunit-mediated effects, with preserved anti-anxiety effects at 30 mg/kg of SH-053-S-CH3 and SH-053-S-CH3-2 0 F. However, all three ligands, dosed at 30 mg/kg, decreased spontaneous locomotor activity, suggesting that sedation may be partly dependent on activity mediated by a 5 -containing GABA A receptors. Hence, it could be of importance to avoid substantial agonist activity at a 5 receptors by candidate anxioselective anxiolytics, if clinical sedation is to be avoided.

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Section: Discussionmentioning

confidence: 99%

Are GABAA Receptors Containing α5 Subunits Contributing to the Sedative Properties of Benzodiazepine Site Agonists?

Savić

Huang

Furtmüller

et al. 2007

Neuropsychopharmacol

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“…The synthesis of 3-methylthio-6-trifl uoromethyl-1,2,4-triazine 31 was achieved by using trifl uoropyruvaldehyde 28 and S-methylthiosemicarbazide 27 as starting materials (Scheme 15 ) [ 24 ]. 3-Aminotriazine 33 was prepared by the condensation of aminoguanidine 32 with dibromoketone 29 , this condensation was non-selective, and 6-trifl uoromethyl-isomer as by-product was formed (Scheme 15 ) [ 25 ]. Microwave assisted reaction of 2-diazo-4,4,4-trifl uoro-3-oxobutanoate 37 with aryl hydrazides in the presence of copper(II)acetate, followed by reaction with ammonium acetate in acetic acid gave the 1,2,4-triazines 38 in modest yield (Scheme 17 ) [ 27 ].…”

Section: The Baltz-schiemann Reactionmentioning

confidence: 99%

Fluorinated Triazines

Русинов¹,

Носова²,

Charushin³

2014

Fluorine in Heterocyclic Chemistry Volume 2

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“…Therefore, current research is revived towards the identification of isoformselective modulators with improved potency and decreased side effects. Merck research laboratory has initiated drug discovery projects aimed at the identification of selective GABA A a 2 /a 3 receptor agonists as anxioselective agents, devoid of sedative effects [77][78][79][80][81][82][83], and a 5 selective inverse agonists as cognitive enhancers [79]. A simple classification of GABA A receptor and their subtypes of pharmacological importance is shown in Table 1.…”

Section: A Predictive Pharmacophore Model For Flavonoidsmentioning

confidence: 99%

Pharmacophore models for GABA_Amodulators: implications in CNS drug discovery

Ghoshal

Vijayan

2010

Expert Opinion on Drug Discovery

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Pharmacophore modeling has now evolved as a mainstay approach for lead generation and optimization in drug discovery programs. Of late, many advances in pharmacophore perception have emerged. Such advancements should be used to confront activity profiling and early stage risk assessment in a high-throughput fashion. Extending such technologies has the potential not only to reduce time and cost, but also to prevent late stage attrition in drug discovery.

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Discovery of Imidazo[1,2-b][1,2,4]triazines as GABA_A α2/3 Subtype Selective Agonists for the Treatment of Anxiety

Cited by 44 publications

References 22 publications

Are GABAA Receptors Containing α5 Subunits Contributing to the Sedative Properties of Benzodiazepine Site Agonists?

Are GABAA Receptors Containing α5 Subunits Contributing to the Sedative Properties of Benzodiazepine Site Agonists?

Fluorinated Triazines

Pharmacophore models for GABA_Amodulators: implications in CNS drug discovery

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Discovery of Imidazo[1,2-b][1,2,4]triazines as GABAA α2/3 Subtype Selective Agonists for the Treatment of Anxiety

Cited by 44 publications

References 22 publications

Are GABAA Receptors Containing α5 Subunits Contributing to the Sedative Properties of Benzodiazepine Site Agonists?

Are GABAA Receptors Containing α5 Subunits Contributing to the Sedative Properties of Benzodiazepine Site Agonists?

Fluorinated Triazines

Pharmacophore models for GABAAmodulators: implications in CNS drug discovery

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Product

Resources

About

Discovery of Imidazo[1,2-b][1,2,4]triazines as GABA_A α2/3 Subtype Selective Agonists for the Treatment of Anxiety

Pharmacophore models for GABA_Amodulators: implications in CNS drug discovery