Pathways

Nizatidine is an histamine H2 receptor antagonist used to treat stomach ulcers and Gastroesophageal Reflux Disease (GERD). After being taken orally, it is absorbed in the GI tract and travels through the blood to get to the stomach epithelium. Ranitidine binds reversibly to the histamine H2 receptor blocking histamine from binding instead. This blocks the downstream Gs cascade which produces cyclic adenosine monophosphate (cAMP) which is an activator for the potassium-hydrogen ATPase pump (H+/K+ ATPase pump). The pump is responsible for secreting hydrogen ions into the stomach lumen increasing the acidity of the stomach environment. By blocking adenylate cyclase signalling pathway from the histamine H2 receptor less hydrogen ions are secreted into the stomach lumen increasing the pH. The less acidic environment doesn't irritate the stomach as much. The H+/K+ ATPase pump can still be activated through gastrin and acetylcholine through the phospholipase C signalling pathway, but blocking the adenylate cyclase pathway helps reduce the acidity.

The N-methyl-D-aspartate receptor (also known as the NMDA receptor or NMDAR), is a glutamate receptor and ion channel found in neurons. The NMDA receptor is one of three types of ionotropic glutamate receptors, the other two being AMPA and kainate receptors. NMDA receptors (NMDARs) are glutamate-gated cation channels with high calcium permeability that play important roles in many aspects of the biology of higher organisms. They are critical for the development of the central nervous system (CNS), generation of rhythms for breathing and locomotion, and the processes underlying learning, memory, and neuroplasticity. Consequently, abnormal expression levels and altered NMDAR function have been implicated in numerous neurological disorders and pathological conditions. NMDAR hypofunction can result in cognitive defects, whereas overstimulation causes excitotoxicity and subsequent neurodegeneration. Therefore, NMDARs are important therapeutic targets for many CNS disorders including stroke, hypoxia, ischemia, head trauma, Huntington’s, Parkinson’s, and Alzheimer’s diseases, epilepsy, neuropathic pain, alcoholism, schizophrenia, and mood disorders. To date, drugs targeting NMDARs have had only limited success clinically due to poor efficacy and unacceptable side effects, including hallucinations, catatonia, ataxia, nightmares, and memory deficits. NMDARs are unique among ligand-gated ion channels in that their activation requires binding of two coagonists, glycine and L-glutamate. Glycine is sometimes cited in the literature as an NMDAR modulator—to set it apart from the agonist L-glutamate, but as explained below, their binding sites are structurally similar and seem to play equivalent roles in receptor activation. Physiologically, however, glycine and glutamate have distinct functions. While L-glutamate is released from specific presynaptic terminals, low concentrations of ambient glycine present at the synapse are thought to be sufficient to allow receptor activation. Because glycine plays a more modulatory role in vivo, while glutamate is the ‘active’, released neurotransmitter, the glycine and glutamate binding sites on the NMDAR represent two distinct therapeutic targets. However, the binding of the ligands is typically not sufficient to open the channel as it may be blocked by Mg2+ ions which are only removed when the neuron is sufficiently depolarized. Thus, the channel acts as a “coincidence detector” and only once both of these conditions are met, the channel opens and it allows positively charged ions (cations) to flow through the cell membrane. Ca2+ flux through NMDA receptors in particular is thought to be critical in synaptic plasticity, a cellular mechanism for learning and memory, due to proteins which bind to and are activated by Ca2+ ions. Overactivation of NMDA receptors, causing excessive influx of Ca2+ can lead to excitotoxicity. Excitotoxicity is implied to be involved in some neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and Huntington's disease.

The N-methyl-D-aspartate receptor (also known as the NMDA receptor or NMDAR), is a glutamate receptor and ion channel found in neurons. The NMDA receptor is one of three types of ionotropic glutamate receptors, the other two being AMPA and kainate receptors. NMDA receptors (NMDARs) are glutamate-gated cation channels with high calcium permeability that play important roles in many aspects of the biology of higher organisms. They are critical for the development of the central nervous system (CNS), generation of rhythms for breathing and locomotion, and the processes underlying learning, memory, and neuroplasticity. Consequently, abnormal expression levels and altered NMDAR function have been implicated in numerous neurological disorders and pathological conditions. NMDAR hypofunction can result in cognitive defects, whereas overstimulation causes excitotoxicity and subsequent neurodegeneration. Therefore, NMDARs are important therapeutic targets for many CNS disorders including stroke, hypoxia, ischemia, head trauma, Huntington’s, Parkinson’s, and Alzheimer’s diseases, epilepsy, neuropathic pain, alcoholism, schizophrenia, and mood disorders. To date, drugs targeting NMDARs have had only limited success clinically due to poor efficacy and unacceptable side effects, including hallucinations, catatonia, ataxia, nightmares, and memory deficits. NMDARs are unique among ligand-gated ion channels in that their activation requires binding of two coagonists, glycine and L-glutamate. Glycine is sometimes cited in the literature as an NMDAR modulator—to set it apart from the agonist L-glutamate, but as explained below, their binding sites are structurally similar and seem to play equivalent roles in receptor activation. Physiologically, however, glycine and glutamate have distinct functions. While L-glutamate is released from specific presynaptic terminals, low concentrations of ambient glycine present at the synapse are thought to be sufficient to allow receptor activation. Because glycine plays a more modulatory role in vivo, while glutamate is the ‘active’, released neurotransmitter, the glycine and glutamate binding sites on the NMDAR represent two distinct therapeutic targets. However, the binding of the ligands is typically not sufficient to open the channel as it may be blocked by Mg2+ ions which are only removed when the neuron is sufficiently depolarized. Thus, the channel acts as a “coincidence detector” and only once both of these conditions are met, the channel opens and it allows positively charged ions (cations) to flow through the cell membrane. Ca2+ flux through NMDA receptors in particular is thought to be critical in synaptic plasticity, a cellular mechanism for learning and memory, due to proteins which bind to and are activated by Ca2+ ions. Overactivation of NMDA receptors, causing excessive influx of Ca2+ can lead to excitotoxicity. Excitotoxicity is implied to be involved in some neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and Huntington's disease.

The N-methyl-D-aspartate receptor (also known as the NMDA receptor or NMDAR), is a glutamate receptor and ion channel found in neurons. The NMDA receptor is one of three types of ionotropic glutamate receptors, the other two being AMPA and kainate receptors. NMDA receptors (NMDARs) are glutamate-gated cation channels with high calcium permeability that play important roles in many aspects of the biology of higher organisms. They are critical for the development of the central nervous system (CNS), generation of rhythms for breathing and locomotion, and the processes underlying learning, memory, and neuroplasticity. Consequently, abnormal expression levels and altered NMDAR function have been implicated in numerous neurological disorders and pathological conditions. NMDAR hypofunction can result in cognitive defects, whereas overstimulation causes excitotoxicity and subsequent neurodegeneration. Therefore, NMDARs are important therapeutic targets for many CNS disorders including stroke, hypoxia, ischemia, head trauma, Huntington’s, Parkinson’s, and Alzheimer’s diseases, epilepsy, neuropathic pain, alcoholism, schizophrenia, and mood disorders. To date, drugs targeting NMDARs have had only limited success clinically due to poor efficacy and unacceptable side effects, including hallucinations, catatonia, ataxia, nightmares, and memory deficits. NMDARs are unique among ligand-gated ion channels in that their activation requires binding of two coagonists, glycine and L-glutamate. Glycine is sometimes cited in the literature as an NMDAR modulator—to set it apart from the agonist L-glutamate, but as explained below, their binding sites are structurally similar and seem to play equivalent roles in receptor activation. Physiologically, however, glycine and glutamate have distinct functions. While L-glutamate is released from specific presynaptic terminals, low concentrations of ambient glycine present at the synapse are thought to be sufficient to allow receptor activation. Because glycine plays a more modulatory role in vivo, while glutamate is the ‘active’, released neurotransmitter, the glycine and glutamate binding sites on the NMDAR represent two distinct therapeutic targets. However, the binding of the ligands is typically not sufficient to open the channel as it may be blocked by Mg2+ ions which are only removed when the neuron is sufficiently depolarized. Thus, the channel acts as a “coincidence detector” and only once both of these conditions are met, the channel opens and it allows positively charged ions (cations) to flow through the cell membrane. Ca2+ flux through NMDA receptors in particular is thought to be critical in synaptic plasticity, a cellular mechanism for learning and memory, due to proteins which bind to and are activated by Ca2+ ions. Overactivation of NMDA receptors, causing excessive influx of Ca2+ can lead to excitotoxicity. Excitotoxicity is implied to be involved in some neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and Huntington's disease.

The N-methyl-D-aspartate receptor (also known as the NMDA receptor or NMDAR), is a glutamate receptor and ion channel found in neurons. The NMDA receptor is one of three types of ionotropic glutamate receptors, the other two being AMPA and kainate receptors. NMDA receptors (NMDARs) are glutamate-gated cation channels with high calcium permeability that play important roles in many aspects of the biology of higher organisms. They are critical for the development of the central nervous system (CNS), generation of rhythms for breathing and locomotion, and the processes underlying learning, memory, and neuroplasticity. Consequently, abnormal expression levels and altered NMDAR function have been implicated in numerous neurological disorders and pathological conditions. NMDAR hypofunction can result in cognitive defects, whereas overstimulation causes excitotoxicity and subsequent neurodegeneration. Therefore, NMDARs are important therapeutic targets for many CNS disorders including stroke, hypoxia, ischemia, head trauma, Huntington’s, Parkinson’s, and Alzheimer’s diseases, epilepsy, neuropathic pain, alcoholism, schizophrenia, and mood disorders. To date, drugs targeting NMDARs have had only limited success clinically due to poor efficacy and unacceptable side effects, including hallucinations, catatonia, ataxia, nightmares, and memory deficits. NMDARs are unique among ligand-gated ion channels in that their activation requires binding of two coagonists, glycine and L-glutamate. Glycine is sometimes cited in the literature as an NMDAR modulator—to set it apart from the agonist L-glutamate, but as explained below, their binding sites are structurally similar and seem to play equivalent roles in receptor activation. Physiologically, however, glycine and glutamate have distinct functions. While L-glutamate is released from specific presynaptic terminals, low concentrations of ambient glycine present at the synapse are thought to be sufficient to allow receptor activation. Because glycine plays a more modulatory role in vivo, while glutamate is the ‘active’, released neurotransmitter, the glycine and glutamate binding sites on the NMDAR represent two distinct therapeutic targets. However, the binding of the ligands is typically not sufficient to open the channel as it may be blocked by Mg2+ ions which are only removed when the neuron is sufficiently depolarized. Thus, the channel acts as a “coincidence detector” and only once both of these conditions are met, the channel opens and it allows positively charged ions (cations) to flow through the cell membrane. Ca2+ flux through NMDA receptors in particular is thought to be critical in synaptic plasticity, a cellular mechanism for learning and memory, due to proteins which bind to and are activated by Ca2+ ions. Overactivation of NMDA receptors, causing excessive influx of Ca2+ can lead to excitotoxicity. Excitotoxicity is implied to be involved in some neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and Huntington's disease.

Nomegestrol is a drug that is not metabolized by the human body as determined by current research and biotransformer analysis. Nomegestrol passes through the liver and is then excreted from the body mainly through the kidney.

Nomifensine, formerly known as Merital capsules, is a dopamine reuptake inhibitor drug that was removed from the market in 1986 for increased incidence of hemolytic anemia. The drug was originally used to treat depression. Nomifensine stimulates the nervous system through the reuptake of norepinephrine and dopamine, which prolongs their duration in the synapse so that they can bind more readily to the receptors. The mechanism is not fully understood, but may be similar to other dopamine reuptake inhibitors where Nomifensine would cross the blood-brain barrier through diffusion. Dopamine is synthesized in the ventral tegmental area of the brain from tyrosine being synthesized into L-dopa by the enzyme Tyrosine 3-monooxygenase . L-Dopa is then synthesized into dopamine with the enzyme aromatic-L-amino-acid decarboxylase. Dopamine then travels to the prefrontal cortex, which is released into the synapse when the neuron is stimulated and fires. Nomifensine binds to the sodium-dependent dopamine transporter, preventing dopamine from re-entering the presynaptic neuron. The dopamine then binds to Dopamine D4 receptors on the postsynaptic membrane. The dopamine D4 receptor activates the Gi protein cascade which inhibits adenylate cyclase. This prevents adenylate cyclase from catalyzing ATP into cAMP.