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1.
ACS Med Chem Lett ; 1(7): 350-4, 2010 Oct 14.
Article in English | MEDLINE | ID: mdl-24900218

ABSTRACT

Amalgamation of the structure-activity relationship of two series of GlyT1 inhibitors developed at Merck led to the discovery of a clinical candidate, compound 16 (DCCCyB), which demonstrated excellent in vivo occupancy of GlyT1 transporters in rhesus monkey as determined by displacement of a PET tracer ligand.

2.
Bioorg Med Chem Lett ; 19(8): 2235-9, 2009 Apr 15.
Article in English | MEDLINE | ID: mdl-19318248

ABSTRACT

A series of heterocyclic sulfonamides have been developed which are potent and selective inhibitors of hGlyT1. SAR studies to optimise the in vitro and in vivo properties are described. Optimisation of the central scaffold resulted in cyclohexane sulfones 28 and 29, which have good PK properties and show promise for further development.


Subject(s)
Glycine Plasma Membrane Transport Proteins/antagonists & inhibitors , Sulfonamides/administration & dosage , Sulfonamides/chemistry , Administration, Oral , Animals , Biological Availability , Glycine Plasma Membrane Transport Proteins/metabolism , Humans , Male , Microsomes, Liver/chemistry , Microsomes, Liver/metabolism , Rats , Rats, Sprague-Dawley , Sulfonamides/metabolism , Triazoles/administration & dosage , Triazoles/chemical synthesis
3.
J Psychopharmacol ; 19(3): 221-7, 2005 May.
Article in English | MEDLINE | ID: mdl-15888506

ABSTRACT

The mouse rotarod test of motor coordination/sedation is commonly used to predict clinical sedation caused by novel drugs. However, past experience suggests that it lacks the desired degree of sensitivity to be predictive of effects in humans. For example, the benzodiazepine, bretazenil, showed little impairment of mouse rotarod performance, but marked sedation in humans. The aim of the present study was to assess whether the mouse beam walking assay demonstrates: (i) an increased sensitivity over the rotarod and (ii) an increased ability to predict clinically sedative doses of benzodiazepines. The study compared the effects of the full benzodiazepine agonists, diazepam and lorazepam, and the partial agonist, bretazenil, on the mouse rotarod and beam walking assays. Diazepam and lorazepam significantly impaired rotarod performance, although relatively high GABA-A receptor occupancy was required (72% and 93%, respectively), whereas beam walking performance was significantly affected at approximately 30% receptor occupancy. Bretazenil produced significant deficits at 90% and 53% receptor occupancy on the rotarod and beam walking assays, respectively. The results suggest that the mouse beam walking assay is a more sensitive tool for determining benzodiazepine-induced motor coordination deficits than the rotarod. Furthermore, the GABA-A receptor occupancy values at which significant deficits were determined in the beam walking assay are comparable with those observed in clinical positron emission tomography studies using sedative doses of benzodiazepines. These data suggest that the beam walking assay may be able to more accurately predict the clinically sedative doses of novel benzodiazepine-like drugs.


Subject(s)
Benzodiazepines/pharmacology , Locomotion/drug effects , Postural Balance/drug effects , Animals , Benzodiazepinones/pharmacology , Central Nervous System Depressants/pharmacology , Diazepam/pharmacology , Dose-Response Relationship, Drug , Ethanol/pharmacology , GABA Agonists/pharmacology , GABA-A Receptor Agonists , Hypnotics and Sedatives/pharmacology , Lorazepam/pharmacology , Male , Mice , Predictive Value of Tests
4.
J Neurosci ; 23(18): 7227-36, 2003 Aug 06.
Article in English | MEDLINE | ID: mdl-12904483

ABSTRACT

Neuronal hyperexcitability is a feature of epilepsy and both inflammatory and neuropathic pain. M currents [IK(M)] play a key role in regulating neuronal excitability, and mutations in neuronal KCNQ2/3 subunits, the molecular correlates of IK(M), have previously been linked to benign familial neonatal epilepsy. Here, we demonstrate that KCNQ/M channels are also present in nociceptive sensory systems. IK(M) was identified, on the basis of biophysical and pharmacological properties, in cultured neurons isolated from dorsal root ganglia (DRGs) from 17-d-old rats. Currents were inhibited by the M-channel blockers linopirdine (IC50, 2.1 microm) and XE991 (IC50, 0.26 microm) and enhanced by retigabine (10 microm). The expression of neuronal KCNQ subunits in DRG neurons was confirmed using reverse transcription-PCR and single-cell PCR analysis and by immunofluorescence. Retigabine, applied to the dorsal spinal cord, inhibited C and Adelta fiber-mediated responses of dorsal horn neurons evoked by natural or electrical afferent stimulation and the progressive "windup" discharge with repetitive stimulation in normal rats and in rats subjected to spinal nerve ligation. Retigabine also inhibited responses to intrapaw application of carrageenan in a rat model of chronic pain; this was reversed by XE991. It is suggested that IK(M) plays a key role in controlling the excitability of nociceptors and may represent a novel analgesic target.


Subject(s)
Neurons, Afferent/metabolism , Pain Management , Pain/metabolism , Potassium Channels/metabolism , Animals , Anthracenes/pharmacology , Anura , CHO Cells , Carbamates/pharmacology , Cells, Cultured , Cricetinae , Disease Models, Animal , Ganglia, Spinal/cytology , Hyperalgesia/physiopathology , Indoles/pharmacology , Male , Neurons, Afferent/cytology , Neurons, Afferent/drug effects , Oocytes/metabolism , Pain Measurement , Patch-Clamp Techniques , Phenylenediamines/pharmacology , Potassium Channel Blockers/pharmacology , Potassium Channels/drug effects , Potassium Channels/genetics , Pyridines/pharmacology , Rats , Rats, Sprague-Dawley , Reverse Transcriptase Polymerase Chain Reaction , Transfection
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