Antalarmin (CP-156,181) is a drug that acts as a
CRH1
The CRH1 EMU, also known as Hexie (simplified Chinese: 和谐号; traditional Chinese: 和諧號; pinyin: Héxié Hào; literally: "Harmony") is a high-speed train operated by China Railway and built by a joint venture between Bombardier Transp ...
antagonist.
Corticotropin-releasing hormone (CRH), also known as
Corticotropin-releasing factor
Corticotropin-releasing factor family, CRF family is a family of related neuropeptides in vertebrates. This family includes corticotropin-releasing hormone (also known as CRF), urotensin-I, urocortin, and sauvagine. The family can be grouped int ...
, is an endogenous peptide hormone released in response to various triggers such as chronic stress and drug addiction. Such triggers result in the release of
corticotropin
Adrenocorticotropic hormone (ACTH; also adrenocorticotropin, corticotropin) is a Peptide, polypeptide tropic hormone produced by and secreted by the Anterior pituitary, anterior pituitary gland. It is also used as a Adrenocorticotropic hormone ...
(ACTH), another hormone involved in the physiological response to stress. Chronic release of CRH and ACTH is believed to be directly or indirectly involved in many of the harmful physiological effects of chronic stress, such as excessive
glucocorticoid
Glucocorticoids (or, less commonly, glucocorticosteroids) are a class of corticosteroids, which are a class of steroid hormones. Glucocorticoids are corticosteroids that bind to the glucocorticoid receptor that is present in almost every vertebr ...
release,
stomach ulcers
Peptic ulcer disease (PUD) is a break in the inner lining of the stomach, the first part of the small intestine, or sometimes the lower esophagus. An ulcer in the stomach is called a gastric ulcer, while one in the first part of the intestines ...
,
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 ...
,
diabetes mellitus
Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ap ...
,
osteoporosis
Osteoporosis is a systemic skeletal disorder characterized by low bone mass, micro-architectural deterioration of bone tissue leading to bone fragility, and consequent increase in fracture risk. It is the most common reason for a broken bone ...
,
depression, and development of
high blood pressure
Hypertension (HTN or HT), also known as high blood pressure (HBP), is a long-term medical condition in which the blood pressure in the arteries is persistently elevated. High blood pressure usually does not cause symptoms. Long-term high bl ...
and consequent cardiovascular problems.
Antalarmin is a non-peptide drug that blocks the CRH1 receptor, and, as a consequence, reduces the release of ACTH in response to chronic stress.
This has been demonstrated in animals to reduce the behavioral responses to stressful situations,
and it is proposed that Antalarmin itself, or more likely newer CRH1 antagonist drugs still under development, could be useful for reducing the adverse health consequences of chronic stress in humans, as well as having possible uses in the treatment of conditions such as anxiety, depression, and drug addiction.
Chemical Structure
The synthesis of CP-154,526, a non-peptide antagonist of the CRH1 receptor, was first described in 1997.
Antalarmin, or CP-156,181, is a close analog that is highly structurally similar and has been shown to be easier to synthesize.
The findings from several chemical, pharmacokinetic and pharmacological studies indicate that the two compounds possess very similar in their properties.
Mechanism of Action
Receptor Binding
As shown in Table 1,
Adenylyl cyclase
Adenylate cyclase (EC 4.6.1.1, also commonly known as adenyl cyclase and adenylyl cyclase, abbreviated AC) is an enzyme with systematic name ATP diphosphate-lyase (cyclizing; 3′,5′-cyclic-AMP-forming). It catalyzes the following reaction:
:A ...
and
cAMP
Camp may refer to:
Outdoor accommodation and recreation
* Campsite or campground, a recreational outdoor sleeping and eating site
* a temporary settlement for nomads
* Camp, a term used in New England, Northern Ontario and New Brunswick to descri ...
assays were used in various functional studies to determine the amount of cAMP inhibition by two CRH1 receptor antagonists: Antalarmin and CP-154,526.
Several receptor binding studies have shown that Antalarmin and CP-154,526 have high affinity for CRH1 receptors, with very similar profiles. Table 2 shows the binding affinities of each compound in various cell lines.
Pharmacokinetics (ADME)
The pharmacokinetics of
CP-154,526
CP-154,526 is a potent and selective antagonist of the corticotropin releasing hormone receptor 1 developed by Pfizer.
CP-154,526 is under investigation for the potential treatment of alcoholism.
See also
* Antalarmin
* Pexacerfont
* Corticotro ...
, a close analog of Antalarmin, have been investigated in male Sprauge-Dawley rats via
intravenous
Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutrie ...
(i.v.) and
oral
The word oral may refer to:
Relating to the mouth
* Relating to the mouth, the first portion of the alimentary canal that primarily receives food and liquid
**Oral administration of medicines
** Oral examination (also known as an oral exam or or ...
(p.o.) routes.
Following a 5 mg/kg dose (i.v.) of CP-154,526, drug concentrations followed a biphasic decline over time. CP-154,526 also demonstrated a large volume of distribution (Vd) at 6.7 L/kg, indicating extensive binding of the drug to tissue in Sprauge-Dawley rats. A plasma clearance of 82 ml/min/kg was observed with an estimated elimination half-life of 1.5 hours. Following p.o. administration at a dose of 10 mg/kg, an average peak plasma concentration (
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 ...
) of 367 ng/mL was determined within 0.5-1 hour of administration. The oral
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%. H ...
was calculated to be 37%, resulting in an estimated hepatic clearance of 63%.
In male Wistar rats given a 5 mg/kg dose (p.o) of CP-154,526, an oral bioavailability of 27% and high volume of distribution at 105 L/kg was determined, with an estimated total clearance (
CLt) of 36 ml/min/kg. CP-154,526 was also observed to cross the blood-brain barrier with good penetrance at a 2.5 brain:plasma ratio 8 hours following oral administration. An extensive pharmacokinetic study of Antalarmin conducted in macaques reported an oral bioavailability of 19%, a total clearance of 4.5 L/hr/kg, and an elimination half-life of 7.8 hours following a 20 mg/kg administration (p.o.). This same dose also resulted in mean Antalarmin plasma levels of 76 ng/ml and CSF levels of 9.8 ng/ml at 3 hours post-administration.
''In vitro'' and ''In vivo'' Research
Results so far have had limited success, with various CRF antagonists being tested, which showed some antidepressant effects, but failed to produce an effect comparable with conventional antidepressant drugs. However more positive results were seen when Antalarmin was combined with an SSRI antidepressant, suggesting a potential for synergistic effect. Encouraging results have also been observed using Antalarmin as a potential treatment for anxiety
and stress-induced hypertension.
Initial studies investigating CP-154,526 showed that the compound binds with high affinity to cortical and pituitary CRH receptors across several species. Additionally, systemic administration of CP-154,526 fully antagonizes the effects of exogenous CRH on ACTH levels, cell firing in the
locus coeruleus
The locus coeruleus () (LC), also spelled locus caeruleus or locus ceruleus, is a nucleus in the pons of the brainstem involved with physiological responses to stress and panic. It is a part of the reticular activating system.
The locus coerule ...
, and fear potentiation in animal models.
However, this potent and selective compound demonstrated low oral bioavailability, and in vitro studies using human liver microsomes predicted high hepatic clearance, deeming the compound unsuitable for clinical development. Nevertheless, many investigators continue to study CP-154,526 and its close analogs (e.g. Antalarmin), using them as tools to examine the physiology of CRH and CRH receptors, as well as to determine the potential therapeutic value of CRH1 antagonists in several CNS and peripheral disorders.
Stress and Anxiety
In vitro studies examining the effects of CRH1 antagonists on the
Hypothalmic-Pituitary-Adrenal (HPA) axis showed that Antalarmin inhibited ACTH release in rat anterior pituitary cells,
as well as inhibited cortisol synthesis and release in human adrenal cells. ''I''n vivo studies revealed that pre-treating rats with Antalarmin inhibited increases in plasma ACTH following CRH injection (i.v.), with no effect on baseline levels.
However, another study demonstrated that 8 weeks of Antalarmin administered twice daily (
i.p.) in rats significantly lowered basal ACTH and corticosterone levels, resulting in reduced adrenocortical responsiveness to ACTH. When Antalarmin was administered to primates, it also inhibited increases in plasma ACTH, as well as prevented the anxiety response produced by a social stressor (e.g. presentation of another male in an unfamiliar environment).
With regards to neurochemical effects, Antalarmin has been shown to inhibit increases in extracellular cortical norepinephrine induced by rat tail pinch'','' suggesting that CHR1 receptors may be implicated in stress-evoked norepinephrine release in the cortex. Antalarmin was also shown to have electrophysiological effects by partially reversing the inhibition of neuronal firing in the
dorsal raphe nucleus
The dorsal raphe nucleus is located on the midline of the brainstem and is one of the raphe nuclei. It has rostral and caudal subdivisions.
* The rostral aspect of the ''dorsal'' raphe is further divided into interfascicular, ventral, ventrolatera ...
that occurs following
intracerebroventricular (i.c.v) administration of CRH''.''
Studies using CRH receptor antagonists such as Antalarmin in anxiety models have shown that these agents produce effects similar to clinically effective anxiolytics.
In conditioned fear models, Antalarmin reduced conditioned freezing behavior, suggesting that it blocked the development and expression of conditioned fear, and implicating CRH1 receptors in both processes''.''
Oral administration of Antalarmin (3–30 mg/kg) also significantly reduced immobility in a rat model of behavioral despair, with effects similar to the
SSRI
Selective serotonin reuptake inhibitors (SSRIs) are a class of drugs that are typically used as antidepressants in the treatment of major depressive disorder, anxiety disorders, and other psychological conditions.
SSRIs increase the extracellul ...
fluoxetine
Fluoxetine, sold under the brand names Prozac and Sarafem, among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. It is used for the treatment of major depressive disorder, obsessive–compulsive disorde ...
''.''
Neurodegeneration
CRH has also been shown to promote
neurodegeneration
A neurodegenerative disease is caused by the progressive loss of structure or function of neurons, in the process known as neurodegeneration. Such neuronal damage may ultimately involve cell death. Neurodegenerative diseases include amyotrophic ...
, suggesting that CRH1 antagonists may have neuroprotective effects.
PC12 cells are derived from the rat adrenal medulla and are extensively used to study neural differentiation. PC12 cells treated with CRH (1-10 nM) showed increased numbers of apoptotic cells and upregulation of the
Fas ligand via
p38 activation, demonstrating the pro-apoptotic effects of CRH. Administration of Antalarmin (10 nM) completely blocked the CRH-induced apoptosis response and inhibited Fas ligand expression''.''
Inflammation
Antalarmin has also been used extensively to study the role of CRH in inflammation.
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 ...
(i.p.) administration of Antalarmin in rats significantly inhibited the inflammation caused by subcutaneous administration of
carrageenan
Carrageenans or carrageenins ( ; ) are a family of natural linear sulfated polysaccharides that are extracted from red edible seaweeds. Carrageenans are widely used in the food industry, for their gelling, thickening, and stabilizing properties. T ...
(a known inflammatory food additive) as measured by leukocyte concentrations''.''
In a rat skin mast cell activation model, pre-treatment with Antalarmin (10 mg/kg, i.v.) inhibited the CRH-stimulated induction of mast cell degranulation'',''
suggesting pro-inflammatory properties of CRH. Antalarmin also blocked the vascular permeability and mast cell degranulation response induced by intradermal
Urocortin
Urocortin is a protein that in humans is encoded by the ''UCN'' gene. Urocortin belongs to the corticotropin-releasing factor (CRF) family of proteins which includes CRF, urotensin I, sauvagine, urocortin II and urocortin III. Urocortin is invol ...
(10 nM)''.''
Collectively, these results indicate that during stress, CRH leads to the activation of skin mast cells through the CRH1 receptor which triggers vasodilation and increased vascular permeability.
Chronic Antalarmin treatment also showed anti-inflammatory effects and has been suggested as having potential uses in the treatment of inflammatory conditions such as
arthritis
Arthritis is a term often used to mean any disorder that affects joints. Symptoms generally include joint pain and stiffness. Other symptoms may include redness, warmth, swelling, and decreased range of motion of the affected joints. In som ...
, as well as stress-induced gastrointestinal ulcers and
irritable bowel syndrome
Irritable bowel syndrome (IBS) is a "disorder of gut-brain interaction" characterized by a group of symptoms that commonly include abdominal pain and or abdominal bloating and changes in the consistency of bowel movements. These symptoms may ...
.
Addiction
Mixed results have been seen in research into the use of Antalarmin and other CRF-1 antagonists in the treatment of drug addiction disorders. Tests of Antalarmin on cocaine use in cocaine-addicted monkeys produced only slight reductions of use that were not statistically significant, however in tests on cocaine-addicted rats, Antalarmin did prevent dose escalation with prolonged use, suggesting that it might stabilize cocaine use and prevent it increasing over time, although without consistently reducing it.
Antalarmin also showed positive effects in reducing withdrawal syndrome from chronic opioid use, and significantly reduced self-administration of ethanol in ethanol-addicted rodents.
Overall, additional research is needed to determine the therapeutic efficacy of Antalarmin and other CRH non-peptide antagonists in anxiety, depression, inflammation, neurodegenerative disease, and addiction.''
''
See also
*
CP-154,526
CP-154,526 is a potent and selective antagonist of the corticotropin releasing hormone receptor 1 developed by Pfizer.
CP-154,526 is under investigation for the potential treatment of alcoholism.
See also
* Antalarmin
* Pexacerfont
* Corticotro ...
*
Pexacerfont
Pexacerfont (INN, previously known as BMS-562,086) is a drug developed by Bristol-Myers Squibb which acts as a CRF1 antagonist.
Corticotropin-releasing factor (CRF), also known as corticotropin-releasing hormone, is an endogenous peptide hormone ...
*
Corticotropin-releasing hormone antagonist A Corticotropin-releasing hormone antagonist (CRH antagonist) is a specific type of receptor antagonist that blocks the receptor sites for corticotropin-releasing hormone, also known as corticotropin-releasing factor (CRF), which synchronizes the b ...
References
{{Anxiolytics
Anxiolytics
Corticotropin-releasing hormone antagonists
Pyrrolopyrimidines