The excitatory amino acid L
The excitatory amino Celecoxib L-glutamate or glutamate mediates most of the excitatory neurotransmission within the mammalian central nervous system (CNS) and has been implicated in numerous peripheral nervous system (PNS) pathways. The excitatory amino acids, including glutamate, are of great physiological importance, playing a role in a variety of neurological, physiological and psychiatric processes, such as synaptic plasticity, motor control, respiration, cardiovascular regulation, sensory perception, and emotional responses. Glutamate acts via at least two distinct classes of receptors. One class is composed of the ionotropic glutamate (iGlu) receptors that act as ligand-gated ion channels. Via activation of the iGlu receptors, glutamate is thought to regulate fast neuronal transmission within the synapse of two connecting neurons in the CNS. The second general type of receptor is the G-protein or second messenger-linked “metabotropic” glutamate (mGlu) receptor. Both types of receptors appear to mediate normal synaptic transmission along excitatory pathways, and also participate in the modification of synaptic connections during development and throughout life., The mGlu receptors belong to the Class C G-protein coupled receptor (GPCR) family. The Class C family of GPCR’s is unique relative to the Class A and Class B GPCRs in that orthosteric ligands bind to a relatively large extracellular amino-terminal domain termed the “Venus Flytrap Domain (VFD)”. Orthosteric agonists are known to stabilize the closed form of the VFD while antagonists favor the open form. Binding of orthosteric agonists lead to large conformational changes of the receptor protein transducing intracellular signals via release of G-proteins. It has been demonstrated that the mGlu receptors are localized either pre- and/or post-synaptically where they can regulate neurotransmitter release. They also modulate the post-synaptic response of neurotransmitters. The metabotropic glutamate 2 (mGlu) receptor is highly expressed primarily in the forebrain and is a presynaptic regulator of glutamate. As such, it has been identified as a novel target for the treatment of anxiety, schizophrenia and pain and has been the focus of intense research over the last decade., , , Positive allosteric modulators (PAMs) offer an alternative approach towards mGlu activation with potentially significant advantages over orthosteric agonists. Furthermore, modulation restricts receptor activation only to relevant tissues in the presence of endogenous agonist (glutamate) and reduces the potential for tachyphylaxis, an effect seen with other GPCR agonists after chronic treatment. Leukotrienes are potent local mediators, playing a major role in inflammatory and allergic responses including arthritis, asthma, psoriasis, and thrombotic disease. Leukotrienes are straight chain eicosanoids produced by the oxidation of arachidonic acid by lipoxygenases in several cell types including eosinophils, neutrophils, mast cells, leukocytes, and macrophages. At the present time, there are two established Class A GPCR receptors for the cysteinyl-leukotrienes (CysLT1 and CysLT2) which the leukotrienes LTC4, LTD4 and LTE4 activate, mediating their pro-inflammatory effects. Each of the CysLT receptors has distinct tissue distributions and associations with physiological responses. Also, the leukotriene LTD4 has a higher affinity for the CysLT1 receptor than the other leukotrienes. Migraine is a debilitating disorder that affects over 2% of the global population, including approximately 18% women and 6% men. This disease has a significant impact on patients’ quality of life and leading to a large societal burden i.e. through lost work time., Neurogenic dural inflammation has been proposed as a source of pain during migraine. Interestingly, there have been some approaches to use leukotriene antagonist drugs to prevent and treat recurrent primary headaches including migraine headaches and prophylactic migraine.