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1.
Br J Pharmacol ; 174(9): 822-835, 2017 05.
Article in English | MEDLINE | ID: mdl-28177520

ABSTRACT

BACKGROUND AND PURPOSE: A body of evidence suggests activation of metabotropic glutamate 2/3 (mGlu2/3 ) receptors would be an effective analgesic in chronic pain conditions. Thus, the analgesic properties of a novel mGlu2/3 receptor agonist prodrug were investigated. EXPERIMENTAL APPROACH: After oral absorption, the prodrug LY2969822 rapidly converts to the brain penetrant, potent and subtype-selective mGlu2/3 receptor agonist LY2934747. Behavioural assessments of allodynia, hyperalgesia and nocifensive behaviours were determined in preclinical pain models after administration of LY2969822 0.3-10 mg·kg-1 . In addition, the ability of i.v. LY2934747 to modulate dorsal horn spinal cord wide dynamic range (WDR) neurons in spinal nerve ligated (SNL) rats was assessed. KEY RESULTS: Following treatment with LY2934747, the spontaneous activity and electrically-evoked wind-up of WDR neurons in rats that had undergone spinal nerve ligation and developed mechanical allodynia were suppressed. In a model of sensitization, orally administered LY2969822 prevented the nociceptive behaviours induced by an intraplantar injection of formalin. The on-target nature of this effect was confirmed by blockade with an mGlu2/3 receptor antagonist. LY2969822 prevented capsaicin-induced tactile hypersensitivity, reversed the SNL-induced tactile hypersensitivity and reversed complete Freund's adjuvant - induced mechanical hyperalgesia. The mGlu2/3 receptor agonist prodrug demonstrated efficacy in visceral pain models, including a colorectal distension model and partially prevented the nocifensive behaviours in the mouse acetic acid writhing model. CONCLUSIONS AND IMPLICATIONS: Following oral administration of the prodrug LY2969822, the mGlu2/3 receptor agonist LY2934747 was formed and this attenuated pain behaviours across a broad range of preclinical pain models.


Subject(s)
Bridged Bicyclo Compounds/administration & dosage , Disease Models, Animal , Hyperalgesia/drug therapy , Prodrugs/administration & dosage , Receptors, Metabotropic Glutamate/agonists , Spiro Compounds/administration & dosage , Administration, Oral , Animals , Bridged Bicyclo Compounds/chemistry , Hyperalgesia/physiopathology , Male , Mice , Mice, Inbred C57BL , Pain Measurement/drug effects , Pain Measurement/methods , Prodrugs/chemistry , Rats , Rats, Sprague-Dawley , Receptors, Metabotropic Glutamate/physiology , Spiro Compounds/chemistry , Treatment Outcome
2.
Bioorg Med Chem Lett ; 27(2): 323-328, 2017 01 15.
Article in English | MEDLINE | ID: mdl-27908761

ABSTRACT

Pyridylmethylsulfonamide series were the first reported example of positive allosteric modulators (PAM) of the mGlu2 receptor. The hydroxyacetophenone scaffold is a second series of mGlu2 PAMs we have identified. This series of molecules are potent mGlu2 potentiators and possess significant CysLT1 (cysteinyl leukotriene receptor 1) antagonist activity, showing in vivo efficacy in a dural plasma protein extravasation (PPE) model of migraine. In this paper, we describe the dual SAR, pharmacokinetics and preclinical in vivo efficacy data for a tetrazole containing hydroxyacetophenone scaffold.


Subject(s)
Drug Discovery , Migraine Disorders/drug therapy , Receptors, Leukotriene/metabolism , Receptors, Metabotropic Glutamate/antagonists & inhibitors , Sulfonamides/pharmacology , Allosteric Regulation/drug effects , Animals , Dogs , Dose-Response Relationship, Drug , Humans , Molecular Structure , Rats , Receptors, Metabotropic Glutamate/agonists , Structure-Activity Relationship , Sulfonamides/administration & dosage , Sulfonamides/chemistry
3.
ACS Med Chem Lett ; 4(6): 560-4, 2013 Jun 13.
Article in English | MEDLINE | ID: mdl-24900709

ABSTRACT

The objective of the described research effort was to identify a novel serotonin and norepinephrine reuptake inhibitor (SNRI) with improved norepinephrine transporter activity and acceptable metabolic stability and exhibiting minimal drug-drug interaction. We describe herein the discovery of a series of 3-substituted pyrrolidines, exemplified by compound 1. Compound 1 is a selective SNRI in vitro and in vivo, has favorable ADME properties, and retains inhibitory activity in the formalin model of pain behavior. Compound 1 thus represents a potential new probe to explore utility of SNRIs in central nervous system disorders, including chronic pain conditions.

4.
J Neurophysiol ; 89(2): 691-703, 2003 Feb.
Article in English | MEDLINE | ID: mdl-12574447

ABSTRACT

The N-methyl-D-aspartate (NMDA) receptor (NMDA-R) has pivotal roles in neural development, learning, memory, and synaptic plasticity. Functional impairment of NMDA-R has been implicated in schizophrenia. NMDA-R activation requires glycine to act on the glycine-B (GlyB) site of the NMDA-R as an obligatory co-agonist with glutamate. Extracellular glycine near NMDA-R is regulated effectively by a glial glycine transporter (GlyT1). Using whole-cell voltage-clamp recordings in prefrontal cortex (PFC) slices, we have shown that exogenous GlyB site agonists glycine and D-serine, or a specific GlyT1 inhibitor N[3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)propyl]sarcosine (NFPS) in the presence of exogenous glycine (10 microM), potentiated synaptically evoked NMDA excitatory postsynaptic currents (EPSCs) in vitro. Furthermore, in urethan-anesthetized rats, microiontophoretic NMDA pulses excite single PFC neurons. When these responses were blocked by approximately 50% to approximately 90% on continuous iontophoretic application of the GlyB site, antagonist (+)HA-966, intravenous NFPS (5 mg/kg), or a GlyB site agonist D-serine (50 mg/kg iv) reversed this (+)HA-966 block. NFPS may elevate endogenous glycine levels sufficiently to displace (+)HA-966 from the GlyB sites of the NMDA-R, thus enabling reactivation of the NMDA-Rs by iontophoretic NMDA applications. D-Serine (50-100 mg/kg iv) or NFPS (1-2 mg/kg iv) alone also augmented NMDA-evoked excitatory responses. These data suggest that direct GlyB site stimulation by D-serine, or blockade of GLYT1 to elevate endogenous glycine to act on unsaturated GlyB sites on NMDA-Rs, potentiated NMDA-R-mediated firing responses in rat PFC. Hence, blockade of GlyT1 to elevate glycine near the NMDA-R may activate hypofunctional NMDA-R, which has been implicated to play a critical role in the pathophysiology of schizophrenia.


Subject(s)
Amino Acid Transport Systems, Neutral/antagonists & inhibitors , Neurons/physiology , Prefrontal Cortex/physiology , Receptors, N-Methyl-D-Aspartate/metabolism , Sarcosine/analogs & derivatives , Amino Acid Transport Systems, Neutral/metabolism , Animals , Excitatory Amino Acid Agonists/pharmacology , Excitatory Postsynaptic Potentials/drug effects , Excitatory Postsynaptic Potentials/physiology , Glycine/pharmacokinetics , Glycine Plasma Membrane Transport Proteins , Iontophoresis , Male , N-Methylaspartate/pharmacology , Organ Culture Techniques , Patch-Clamp Techniques , Prefrontal Cortex/cytology , Pyrrolidinones/pharmacology , Rats , Rats, Sprague-Dawley , Sarcosine/pharmacology , Serine/pharmacology
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