Neuroscience Glossary

Neurogen Corporation

Agonist

A compound or drug which activates or facilitates a receptor on the post-synaptic cell.

AIDD (Accelerated Intelligent Drug Discovery):

Neurogen's AIDD program brings the power of massive parallel processing made possible by robotics to the project of discovering new drugs. Drug discovery is essentially a trial and error process of trying different compounds with varying chemical structures against a known problem to discover what types of chemical structures treat the problem. Consequently, by increasing exponentially the numbers of compounds generated by employing combinatorial chemistry techniques and likewise increasing the screening capacity with high-throughput screening to determine the effectiveness of the compounds, the arduous trial and error process can be accelerated greatly.

Another critical component of the process is powerful computer informatic capabilities to process and manage the volumes of data generated and to aid in the decision making process of what to make and screen next.

Assembled together, the combinatorial chemistry, high-throughput screening and the robotics and informatics capabilities of AIDD provide the medicinal chemist with a very powerful tool to help in discovering innovative drugs targeted at many human diseases.

Antagonist:

A compound or drug which blocks or inhibits the effects of a neurotransmitter on receptor activation in the post-synaptic cell.

Blood-Brain Barrier:

The blood-brain barrier is a selectively permeable membrane made up of capillaries more tightly packed than throughout the rest of the body. These closely packed capillaries supply blood to the brain and spinal cord. Large molecules cannot permeate through the narrow spaces, however fat soluble (lipophilic) molecules can dissolve through the capillary cell membranes and are absorbed into the brain.

 

Combinatorial Chemistry:

Combinatorial chemistry is an automated process used in Neurogen's AIDD program to combine chemical fragments to synthesize target compounds rapidly. As an indication of the power of this technique, a traditional chemist at a laboratory bench is able to synthesize 50-150 new compounds per year, while Neurogen's combinatorial techniques can synthesize one million compounds per year. Neurogen has chosen to bias, or direct, the library of compounds to be generated with the maximum similarity around certain chemical motifs known to be active in research areas of interest to Neurogen, in order to increase the likelihood of finding active and useful compounds. The combinatorial process does not completely remove a traditional chemist, however, as chemists are needed to make the chemical fragments and to design new automated synthesis methods. In order to determine which new compounds are useful, high-throughput screening is used.

CRH (corticotrophin releasing hormone) or CRF (corticotrophin releasing factor):

CRH or CRF, a type of neurotransmitter, controls the secretion of other stress-related hormones in the pituitary. Evidence exists that indicates that CRF is oversecreted in depression, perhaps contributing to some of the symptoms of depression such as decreased libido, insomnia, and decreased appetite, and CRF also may be involved in anxiety disorders. Neurogen is developing CRF antagonists to block the effects of CRF that may underlie several diseases.

Dopamine:

A neurotransmitter of the catecholamine family, which also includes norepinephrine and epinephrine. Dopamine is involved in emotional behavior, and at least 5 receptor subtypes have been identified. Excess levels of dopamine are thought to cause schizophrenia, while low dopamine levels results in the shaking and lack of motor control seen in Parkinson's disease. Neurogen is developing dopamine D4 receptor subtype specific antagonists. Current evidence suggests that there may be more dopamine D4 receptors in the brains of schizophrenic patients than normal.

Federal Drug Administration (FDA) Approval Process:

The FDA approval process begins with an Investigational New Drug (IND) Application which contains all the preclinical studies conducted using the drug, as well as chemistry and manufacturing data. These include safety and toxicology studies using the drug in animals, and any efficacy studies that have been conducted in animals. Thirty days after submission, if the company has received no questions or requests for further information, the company may begin Phase I studies in humans.

Phase I studies are designed on a small scale to show that the drug is safe in humans. Phase I studies examine the pharmacokinetic and pharmacological effects of the drug, mechanism of action and seek to gain early evidence of effectiveness. Ultimately, all the information gleaned from a well designed Phase I trial will aid in developing a well designed Phase II trial. Phase Ia studies examine how the body reacts to a single, one-time dose of the drug in a monitored situation, usually involving healthy volunteers without the condition that the drug will be indicated for. As each dose is tested in a predetermined number of people, the trial progresses to the next dosing level with a different group of volunteers. Phase Ib trials examine how the body reacts to multiple doses of the drug over a period of time, from a few days to a few weeks. The average length of time that a compound is in Phase I testing is about one year.

Phase II testing looks at the efficacy of a drug, provided that it has proven safe in Phase I testing. Phase II testing is conducted in a relatively small number of patients having the condition the drug is indicated for, using several doses that, based on the data obtained in Phase I, are hypothesized to be efficacious doses. A placebo is also tested to obtain a baseline value for the comparison of drug effectiveness. Phase II testing takes from several months to 3 years.

Phase III testing is efficacy testing in a large population of patients who are more representative of the population as a whole, and often compares the experimental drug to other approved drugs. Testing takes on average 24 months, with the FDA requiring a longer period for drugs to treat some indications.

New Drug Application (NDA): When a drug has completed all three stages of testing, the company files an NDA with the FDA. Once the FDA has reviewed all the data from clinical testing, it can approve the NDA for the drug to be marketed and sold, or it can schedule a hearing to bring experts together to comment on the clinical data and the drug to be reviewed. Sometimes an additional study is requested to clarify the scientific data to show more proof that the drug works, or to compare the drug to existing medications for treating the disease.

Phase IV Often after a drug's approval, post marketing surveillance studies, or Phase IV studies are conducted to learn more about the drug's risks, benefits, optimal use, and how it compares to competitors.

GABA (gamma aminobutyric acid):

An inhibitory neurotransmitter, which when at lower than normal levels, may be responsible for some types of anxiety. Evidence for this is given by the fact that anti-anxiety drugs such as the benzodiazepines Valium and Librium bind to the receptor and increase its response to GABA. Through Neurogen's knowledge of the individual receptor subtypes of the GABA receptor, the Company is able to identify which subtypes or combinations of subtypes are responsible for drowsiness, cognitive impairments, anxiety and interaction with alcohol. Neurogen is able to design receptor subtype specific drugs without the side effects that other non-subtype selective GABA agonist drugs produce.

Galanin:

Galanin is neuropeptide neurotransmitter whose receptors are found in areas of the brain responsible for feeding, as well as for learning and memory. It is theorized that a small molecule drug which blocks the effects of galanin might be useful in reducing the body's appetite for fatty food, as well as modulating acetylcholine, a neurotransmitter implicated in Alzheimer's disease.

High-Throughput Screening:

High-throughput screening is a technique of rapidly screening for biological effects in very large numbers of compounds generated in the combinatorial chemistry branch of Neurogen's AIDD program. High-throughput screening tests examine whether a compound binds to a receptor of interest, whether the compound produces a functional response in the receptor, and other tests on a small scale. High-throughput screening is a first-pass test affording a quick initial look at the efficacy of a compound.

Neuron:

The nerve cell that serves as the information processing and transmitting element of the nervous system. It is made up of the soma, or cell body; dendrites which receive messages via neurotransmitters from other neurons across the synapse; and the axon which transmits the message from one cell across the synapse to another cell.

Neuropeptide Y (NPY):

NPY is a peptide from the pancreatic polypeptide family, with at least six NPY receptor subtypes found in differing concentrations throughout the brain. Researchers have shown that NPY is a potent stimulator of eating by injecting NPY into the ventricles of the brain, whereby it stimulates eating to the point of obesity in several laboratory species. By making an antagonist drug that blocks the binding of NPY to a receptor, Neurogen is seeking to reduce appetite as well as increase metabolism.

Neurotransmitter:

A chemical that is secreted by the terminal buttons of an axon into a synapse and produces an excitatory or inhibitory post-synaptic electrical charge in the specific receptors in the membrane of the post synaptic, or receiving cell. Neurogen is developing drugs that work with the GABA, Dopamine, Neuropeptide Y, Corticotrophin Releasing Factor, and other neurotransmitter systems.

Pharmacokinetics:

Pharmacokinetics examines the effects of the body on a drug, specifically examining issues such as how quickly a drug is absorbed into the blood and how different dosages affect the absorption, how the drug is distributed into organs or tissues the body, how the body metabolizes the drug and whether what the drug is changed into by the body is active, as well how long it takes the body to metabolize half of the drug (the drug's half-life), and how long it takes the drug to clear the body and be excreted.

Pharmacology:

Pharmacology examines the effects of the drug on the body, looking at such issues as how the drug works, its safety, whether it affects one organ or area of the body more than another, and what common adverse experiences (AEs) are associated with its use.

Receptor:

Found in the post-synaptic side of the synapse, a receptor consists of a protein molecule embedded in the membrane of the cell which contains active sites that bind to a particular chemical or neurotransmitter. When a receptor is stimulated, changes take place either at the receptor through chemically gated ion channels which change the electrical potential of the cell, or within the cell using transmembrane transduction which activates second messengers to carry out secondary effects.

Receptor Subtypes:

A receptor is made up of folded protein sections, or subtypes, forming the central pore of the receptor which opens and closes as the receptor is stimulated. Each subtype may have active binding sites which change the activity of the receptor through its response to other neurotransmitters.

Schizophrenia:

Affecting approximately 1 percent of the population worldwide, schizophrenia is a disconnection from reality caused by disorganization of the mind's functions, not a split, or multiple personality. High levels of the neurotransmitter dopamine are thought to be the cause of the disease. The symptoms of schizophrenia are divided into two categories: positive and negative. Positive symptoms consist of hallucinations, thought disorders and delusions. Negative symptoms consist of the absence of normal behaviors, such as social withdrawal, flattened emotional response, inability to experience pleasure, and lack of speech.

Synapse:

The synapse is a junction between an axon of one neuron and the cell membrane of another neuron. Neurotransmitters travel across the space, or synaptic cleft, from the pre-synaptic neuron and are received by receptors on the opposite cell membrane, or post-synaptic neuron.

Virtual Library:

Utililized in Neurogen's AIDD Program, the virtual library consists of all the molecules for which the ingredients, or starting materials, are on hand and for which the routes of synthesis are known. The virtual library consists of compounds not yet made, but which could be made if the informatics component of AIDD indicates a compound would be of interest for a target. Currently Neurogen's virtual library consists of over 400 million compounds.