Deramciclane (EGIS-3886) is a non-

benzodiazepine Benzodiazepines (BZD, BDZ, BZs), sometimes called "benzos", are a class of depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed to treat conditions such as anxiety disorders, ...

-type

anxiolytic An anxiolytic (; also antipanic or antianxiety agent) is a medication or other intervention that reduces anxiety. This effect is in contrast to anxiogenic agents which increase anxiety. Anxiolytic medications are used for the treatment of anxiet ...

drug to treat various types of

anxiety disorders Anxiety disorders are a cluster of mental disorders characterized by significant and uncontrollable feelings of anxiety and fear such that a person's social, occupational, and personal function are significantly impaired. Anxiety may cause physi ...

. Deramciclane is a unique alternative to current anxiolytics on the market because it has a novel chemical structure and target. It acts as an

antagonist An antagonist is a character in a story who is presented as the chief foe of the protagonist. Etymology The English word antagonist comes from the Greek ἀνταγωνιστής – ''antagonistēs'', "opponent, competitor, villain, enemy, ri ...

at the 5-HT_2A

receptor Receptor may refer to: *Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse *Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a n ...

, as an

inverse agonist In pharmacology, an inverse agonist is a drug that binds to the same receptor as an agonist but induces a pharmacological response opposite to that of the agonist. A neutral antagonist has no activity in the absence of an agonist or inverse ago ...

at the 5-HT_2C receptor, and as a

GABA reuptake inhibitor A GABA reuptake inhibitor (GRI) is a type of drug which acts as a reuptake inhibitor for the neurotransmitter gamma-Aminobutyric acid (GABA) by blocking the action of the gamma-Aminobutyric acid transporters (GATs). This in turn leads to incre ...

. The two

serotonin receptor 5-HT receptors, 5-hydroxytryptamine receptors, or serotonin receptors, are a group of G protein-coupled receptor and ligand-gated ion channels found in the central and peripheral nervous systems. They mediate both excitatory and inhibitory ne ...

s are

G protein-coupled receptor G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily-related p ...

s and are two of the main excitatory serotonin receptor types. Their excitation has been implicated in

anxiety Anxiety is an emotion which is characterized by an unpleasant state of inner turmoil and includes feelings of dread over anticipated events. Anxiety is different than fear in that the former is defined as the anticipation of a future threat wh ...

and mood. Deramciclane does not affect

CYP3A4 Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine. It oxidizes small foreign organic molecules ( xenobiotics), such as toxins or drugs, so that they can be removed from ...

activity in metabolizing other drugs, but it is a weak inhibitor of

CYP2D6 Cytochrome P450 2D6 (CYP2D6) is an enzyme that in humans is encoded by the ''CYP2D6'' gene. ''CYP2D6'' is primarily expressed in the liver. It is also highly expressed in areas of the central nervous system, including the substantia nigra. CYP2D ...

. Some studies also show the drug to have moderate affinity to dopamine D2 receptors and low affinity to

dopamine receptor D1 Dopamine receptor D1, also known as DRD1. It is one of the two types of D1-like receptor family - receptors D1 and D5. It is a protein that in humans is encoded by the DRD1 gene. Tissue distribution D1 receptors are the most abundant kind of d ...

. Researchers are looking for alternatives to benzodiazepines for anxiolytic use because benzodiazepine drugs have

sedative A sedative or tranquilliser is a substance that induces sedation by reducing irritability or excitement. They are CNS depressants and interact with brain activity causing its deceleration. Various kinds of sedatives can be distinguished, but ...

and

muscle relaxant A muscle relaxant is a drug that affects skeletal muscle function and decreases the muscle tone. It may be used to alleviate symptoms such as muscle spasms, pain, and hyperreflexia. The term "muscle relaxant" is used to refer to two major therap ...

side effects.

Commercial history

Deramciclane was discovered by EGIS Pharmaceuticals Ltd in Budapest, Hungary. In 2000, EGIS signed over exclusive rights to Orion Pharma to further develop, register, and market deramciclane. Successful pre-clinical, Phase I, and Phase II trials looked promising to the company and its investors even up until the third quarter of 2002.Blow to Orion as deramciclane fails in Phase III anxiety studies, 2003 http://www.thepharmaletter.com/article/blow-to-orion-as-deramciclane-fails-in-phase-iii-anxiety-studies Phase I studies show little to no side effects of deramciclane. Phase II studies show little to no side effects and statistically significant improvement on the

Hamilton Anxiety Rating Scale The Hamilton Anxiety Rating Scale (HAM-A) is a psychological questionnaire used by clinicians to rate the severity of a patient's anxiety Anxiety is an emotion which is characterized by an unpleasant state of inner turmoil and includes feelin ...

in response to daily 60 mg doses, but not in response to daily 10 or 30 mg doses. Finally, in February, 2003, deramciclane development for use against general anxiety disorder (GAD) was discontinued during Phase III trials due to clinically insignificant results compared to placebo groups.

Pharmacokinetics

There have been several clinical studies to examine the

pharmacokinetics Pharmacokinetics (from Ancient Greek ''pharmakon'' "drug" and ''kinetikos'' "moving, putting in motion"; see chemical kinetics), sometimes abbreviated as PK, is a branch of pharmacology dedicated to determining the fate of substances administered ...

of deramciclane, which can readily cross the

blood–brain barrier The blood–brain barrier (BBB) is a highly selective semipermeable border of endothelial cells that prevents solutes in the circulating blood from ''non-selectively'' crossing into the extracellular fluid of the central nervous system where ne ...

. Overall, studies show that deramciclane follows linear pharmacokinetics in humans with oral daily doses ranging from 3–150 mg and twice daily doses ranging from 10–60 mg. Additionally, no differences have been found in adsorption, distribution, metabolism, or elimination when an oral dose is administered in tablet or capsule form. Deramciclane is rapidly absorbed from the gastrointestinal tract. Studies show that the drug can be detected in plasma as quickly as 20 minutes after dosing. Deramciclane demonstrates a Tmax of 2–4 hours and is unaffected by dosage. The

Cmax CMAX is a bus rapid transit (BRT) service in Central Ohio, operated by the Central Ohio Transit Authority (COTA). The line begins in Downtown Columbus, traveling northeast to Westerville. CMAX is Central Ohio's first bus rapid transit line; it ...

at this time is approximately 140 ng/mL. A typical PTF (peak trough fluctuation) is 70-80% over four weeks of administration, and is unaffected by dose. The oral tablet of deramciclane yields a

bioavailability In pharmacology, bioavailability is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation. By definition, when a medication is administered intravenously, its bioavailability is 100%. Ho ...

of 36% on average, which is considered decent enough for oral administration and avoid the necessity of a more invasive route. The pharmacokinetics of deramciclane are also studied in rats, mice, rabbits, and dogs. Rat and rabbits show the fastest metabolism rates of the drug, and dogs are the only animals to show non-linear pharmacokinetics of deramciclane.

Phase I metabolism Drug metabolism is the metabolic breakdown of drugs by living organisms, usually through specialized enzymatic systems. More generally, xenobiotic metabolism (from the Greek xenos "stranger" and biotic "related to living beings") is the set ...

in rat

hepatocytes A hepatocyte is a cell of the main parenchymal tissue of the liver. Hepatocytes make up 80% of the liver's mass. These cells are involved in: * Protein synthesis * Protein storage * Transformation of carbohydrates * Synthesis of cholesterol, ...

is similar enough to that in humans that the rat can be used as a predictive model for human metabolism of deramciclane. In rats, the Tmax is found to be 0.5 hours after a single 10 mg/kg dose and the half-life of deramciclane is about 3.5-5.5 hours. As expected, deramciclane reaches greatest peak plasma concentrations with intravenous administration, followed by

intraperitoneal The peritoneum is the serous membrane forming the lining of the abdominal cavity or coelom in amniotes and some invertebrates, such as annelids. It covers most of the intra-abdominal (or coelomic) organs, and is composed of a layer of mesothel ...

, then oral administration with the lowest peak plasma concentration. Studies assessing the elimination half-life of deramciclane point to a range of 20–32 hours for T1/2. The elimination half-life appears to increase with dosage. There is some evidence for accumulation of deramciclane, though it is a topic of debate.

Metabolism

It is important to understand the metabolism pathway of a drug to better understand its pharmacology, toxicity, and animal model predictability. The metabolism pathway in humans is not entirely clear, though certain reactions have been shown to happen in the breakdown of deramciclane. For example, deramciclane undergoes side chain modification and

oxidation Redox (reduction–oxidation, , ) is a type of chemical reaction in which the oxidation states of substrate change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is the gain of electrons or ...

at multiple positions on the molecule. The side chain reaction forms phenylborneol and N-desmethyl deramciclane which is the active metabolite of deramciclane. Oxidation of the molecule results in many hydroxy-, carboxy-, and N-oxide derivatives.

Food interaction

Also important to the pharmacokinetics of a drug is its interactions with food during adsorption because this affects the dosage required. Deramciclane is an acid-labile compound. Acid-labile compounds are more easily broken down in acidic environments, so the decrease in stomach pH as a result of the presence of food could have adverse effects on the bioavailability of deramciclane. Clinical studies investigating the effects of food or lack thereof on deramciclane adsorption show that there is a statistically significant, but not clinically relevant, increase in bioavailability of deramciclane when administered with food because the point of critical instability of deramciclane is relatively low at a pH of 2. The presence of food does not affect deramciclane's elimination

half-life Half-life (symbol ) is the time required for a quantity (of substance) to reduce to half of its initial value. The term is commonly used in nuclear physics to describe how quickly unstable atoms undergo radioactive decay or how long stable ...

(T1/2) or mean

residence time The residence time of a fluid parcel is the total time that the parcel has spent inside a control volume (e.g.: a chemical reactor, a lake, a human body). The residence time of a set of parcels is quantified in terms of the frequency distribu ...

(MRT).

Safety and side effects

All clinical studies have shown that deramciclane is well tolerated in humans at dosages ranging between 0.2–150 mg. All reported side effects were mild-moderate with the most common side effect being headache and dizziness. No severe side effects were reported in any clinical trial, and no side effects were found to be dose-dependent. Trial participants showed no significant increases in liver

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...

activity and no changes in ECGs, systolic blood pressure, diastolic blood pressure,

HDL cholesterol High-density lipoprotein (HDL) is one of the five major groups of lipoproteins. Lipoproteins are complex particles composed of multiple proteins which transport all fat molecules (lipids) around the body within the water outside cells. They are t ...

, or

LDL cholesterol Low-density lipoprotein (LDL) is one of the five major groups of lipoprotein that transport all fat molecules around the body in extracellular water. These groups, from least dense to most dense, are chylomicrons (aka ULDL by the overall densi ...

levels. Another advantage to deramciclane is that it did not produce any withdrawal effects after long-term studies, like other anxiolytics do.

References