Phosphodiesterase inhibitor
Encyclopedia
A phosphodiesterase inhibitor is a drug
that blocks one or more of the five subtypes of the enzyme
phosphodiesterase
(PDE), therefore preventing the inactivation of the intracellular second messengers cyclic adenosine monophosphate
(cAMP) and cyclic guanosine monophosphate
(cGMP) by the respective PDE subtype(s).
Methylated xanthines act as both
But different analogues show varying potency at the numerous subtypes, and a wide range of synthetic xanthine derivatives
(some nonmethylated) have been developed in the search for compounds with greater selectivity for phosphodiesterase enzyme
or adenosine receptor
subtypes.
PDE3
is sometimes referred to as cGMP-inhibited phosphodiesterase.
PDE4 is the major cAMP-metabolizing enzyme found in inflammatory and immune cells. PDE4 inhibitors have proven potential as anti-inflammatory drugs, especially in inflammatory pulmonary diseases such as asthma
, COPD
, and rhinitis
. They suppress the release of cytokine
s and other inflammatory signals, and inhibit the production of reactive oxygen species. PDE4 inhibitors may have antidepressive effects and have also recently been proposed for use as antipsychotic
s.
On October 26, 2009, The University of Pennsylvania reported that researchers at their institution had discovered a link between elevated levels of PDE4 (and therefore decreased levels of cAMP) in sleep deprived mice. Treatment with a PDE4 inhibitor raised the deficient cAMP levels and restored some functionality to Hippocampus-based memory functions.
, an opium
alkaloid
, has been reported to act as a PDE10 inhibitor.
PDE10A is almost exclusively expressed in the striatum
and subsequent increase in cAMP and cGMP after PDE10A inhibition (e.g. by papaverine
) is "a novel therapeutic avenue in the discovery of antipsychotics".
Medication
A pharmaceutical drug, also referred to as medicine, medication or medicament, can be loosely defined as any chemical substance intended for use in the medical diagnosis, cure, treatment, or prevention of disease.- Classification :...
that blocks one or more of the five subtypes of the enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
phosphodiesterase
Phosphodiesterase
A phosphodiesterase is any enzyme that breaks a phosphodiester bond. Usually, people speaking of phosphodiesterase are referring to cyclic nucleotide phosphodiesterases, which have great clinical significance and are described below...
(PDE), therefore preventing the inactivation of the intracellular second messengers cyclic adenosine monophosphate
Cyclic adenosine monophosphate
Cyclic adenosine monophosphate is a second messenger important in many biological processes...
(cAMP) and cyclic guanosine monophosphate
Cyclic guanosine monophosphate
Cyclic guanosine monophosphate is a cyclic nucleotide derived from guanosine triphosphate . cGMP acts as a second messenger much like cyclic AMP...
(cGMP) by the respective PDE subtype(s).
History
The different forms or subtypes of phosphodiesterase were initially isolated from rat brains by Uzunov and Weiss in 1972 and were soon afterwards shown to be selectively inhibited in the brain and in other tissues by a variety of drugs. The potential for selective phosphodiesterase inhibitors as therapeutic agents was predicted as early as 1977 by Weiss and Hait. This prediction meanwhile has proved to be true in a variety of fields.Nonselective phosphodiesterase inhibitors
Methylated xanthines and derivatives:- caffeineCaffeineCaffeine is a bitter, white crystalline xanthine alkaloid that acts as a stimulant drug. Caffeine is found in varying quantities in the seeds, leaves, and fruit of some plants, where it acts as a natural pesticide that paralyzes and kills certain insects feeding on the plants...
, a minor stimulantStimulantStimulants are psychoactive drugs which induce temporary improvements in either mental or physical function or both. Examples of these kinds of effects may include enhanced alertness, wakefulness, and locomotion, among others... - aminophyllineAminophyllineAminophylline is a bronchodilator. It is a compound of the bronchodilator theophylline with ethylenediamine in 2:1 ratio. The ethylenediamine improves solubility, and the aminophylline is usually found as a dihydrate-Properties:...
- IBMXIBMXIBMX, 3-isobutyl-1-methylxanthine, like other methylated xanthine derivatives, is both a# competitive nonselective phosphodiesterase inhibitor which raises intracellular cAMP, activates PKA, inhibits TNF-alpha and leukotriene synthesis, and reduces inflammation and innate immunity and#...
(3-isobutyl-1-methylxanthine), used as investigative tool in pharmacological research - paraxanthineParaxanthineParaxanthine, or 1,7-dimethylxanthine, is a dimethyl derivative of xanthine, structurally related to caffeine. Like caffeine, paraxanthine is a psychoactive central nervous system stimulant...
- pentoxifylline, a drug that has the potential to enhance circulation and may have applicability in treatment of diabetes, fibrotic disorders, peripheral nerve damage, and microvascular injuries
- theobromineTheobromineTheobromine , also known as xantheose, is a bitter alkaloid of the cacao plant, with the chemical formula C7H8N4O2. It is found in chocolate, as well as in a number of other foods, including the leaves of the tea plant, and the kola nut...
- theophyllineTheophyllineTheophylline, also known as dimethylxanthine, is a methylxanthine drug used in therapy for respiratory diseases such as COPD and asthma under a variety of brand names. Because of its numerous side-effects, the drug is now rarely administered for clinical use. As a member of the xanthine family, it...
, a bronchodilatorBronchodilatorA bronchodilator is a substance that dilates the bronchi and bronchioles, decreasing resistance in the respiratory airway and increasing airflow to the lungs. Bronchodilators may be endogenous , or they may be medications administered for the treatment of breathing difficulties...
Methylated xanthines act as both
- competitive nonselective phosphodiesterase inhibitors which raise intracellular cAMPCyclic adenosine monophosphateCyclic adenosine monophosphate is a second messenger important in many biological processes...
, activate PKACAMP-dependent protein kinaseIn cell biology, Protein kinase A refers to a family of enzymes whose activity is dependent on cellular levels of cyclic AMP . PKA is also known as cAMP-dependent protein kinase...
, inhibit TNF-alphaTNF inhibitorTumor necrosis factor promotes the inflammatory response, which in turn causes many of the clinical problems associated with autoimmune disorders such as rheumatoid arthritis, ankylosing spondylitis, Crohn's disease, psoriasis, hidradenitis suppurativa and refractory asthma. These disorders are...
and leukotrieneLeukotrieneLeukotrienes are fatty signaling molecules. They were first found in leukocytes . One of their roles is to trigger contractions in the smooth muscles lining the trachea; their overproduction is a major cause of inflammation in asthma and allergic rhinitis...
synthesis, and reduce inflammationAnti-inflammatoryAnti-inflammatory refers to the property of a substance or treatment that reduces inflammation. Anti-inflammatory drugs make up about half of analgesics, remedying pain by reducing inflammation as opposed to opioids, which affect the central nervous system....
and innate immunity and - nonselective adenosine receptorAdenosine receptorThe adenosine receptors are a class of purinergic receptors, G protein-coupled receptors with adenosine as endogenous ligand.-Pharmacology:...
antagonists
But different analogues show varying potency at the numerous subtypes, and a wide range of synthetic xanthine derivatives
Xanthine
Xanthine , is a purine base found in most human body tissues and fluids and in other organisms. A number of stimulants are derived from xanthine, including caffeine and theobromine....
(some nonmethylated) have been developed in the search for compounds with greater selectivity for phosphodiesterase enzyme
Phosphodiesterase
A phosphodiesterase is any enzyme that breaks a phosphodiester bond. Usually, people speaking of phosphodiesterase are referring to cyclic nucleotide phosphodiesterases, which have great clinical significance and are described below...
or adenosine receptor
Adenosine receptor
The adenosine receptors are a class of purinergic receptors, G protein-coupled receptors with adenosine as endogenous ligand.-Pharmacology:...
subtypes.
PDE2 selective inhibitors
- EHNAEHNAEHNA is a phosphodiesterase inhibitor that selectively inhibits phosphodiesterase type 2 ....
(erythro-9-(2-hydroxy-3-nonyl)adenine) - AnagrelideAnagrelideAnagrelide is a drug used for the treatment of essential thrombocytosis , or overproduction of blood platelets. It also has been used in the treatment of chronic myeloid leukemia. -Mechanism:...
PDE3 selective inhibitors
- EnoximoneEnoximoneEnoximone is an imidazole phosphodiesterase inhibitor. It is used in the treatment of congestive heart failure. Selective for phosphodiesterase 3...
and milrinoneMilrinoneMilrinone is a phosphodiesterase 3 inhibitor. It potentiates the effect of cyclic adenosine monophosphate .Milrinone also enhances contraction of the left ventricle by increasing Ca2+-ATPase activity on the cardiac sarcoplasmic reticulum...
are used clinically for short-term treatment of cardiac failure. These drugs mimic sympatheticSympathetic nervous systemThe sympathetic nervous system is one of the three parts of the autonomic nervous system, along with the enteric and parasympathetic systems. Its general action is to mobilize the body's nervous system fight-or-flight response...
stimulation and increase cardiac outputCardiac outputCardiac output is the volume of blood being pumped by the heart, in particular by a left or right ventricle in the time interval of one minute. CO may be measured in many ways, for example dm3/min...
.
PDE3
PDE3
PDE3 is a phosphodiesterase. The PDEs belong to at least eleven related gene families, which are different in their primary structure, substrate affinity, responses to effectors, and regulation mechanism....
is sometimes referred to as cGMP-inhibited phosphodiesterase.
PDE4 selective inhibitors
- MesembrineMesembrineMesembrine is an alkaloid present in Sceletium tortuosum. Mesembrine acts as a serotonin reuptake inhibitor. Mesembrine may contribute to the antidepressant effects of kanna....
, an alkaloid from the herb Sceletium tortuosumSceletium tortuosumSceletium tortuosum is a succulent herb commonly found in South Africa, which is also known as Kanna, Channa, Kougoed - which literally means, 'chew things/goodies' or 'something to chew'... - RolipramRolipramRolipram is a PDE4-inhibitor. Like most PDE4-inhibitors, it is an anti-inflammatory drug. Rolipram is being studied as a possible alternative to current antidepressants. Recent studies show that rolipram may have antipsychotic effects...
, used as investigative tool in pharmacological research - IbudilastIbudilastIbudilast is an antiinflammatory drug used mainly in Japan, which acts as a phosphodiesterase inhibitor, inhibiting the PDE-4 subtype to the greatest extent, but also showing significant inhibition of other PDE subtypes.Ibudilast has bronchodilator, vasodilator and neuroprotective effects, and is...
, a neuroprotective and bronchodilator drug used mainly in the treatment of asthma and stroke. It inhibits PDE4 to the greatest extent, but also shows significant inhibition of other PDE subtypes, and so acts as a selective PDE4 inhibitor or a non-selective phosphodiesterase inhibitor, depending on the dose. - PiclamilastPiclamilastPiclamilast , is a selective PDE4 inhibitor. It is comparable to other PDE4 inhibitors for its anti-inflammatory effects. It has been investigated for its applications to the treatment of conditions such as chronic obstructive pulmonary disease, bronchopulmonary dysplasia and asthma...
, a more potent inhibitor than rolipram. - LuteolinLuteolinLuteolin is a yellow crystalline compound. It is a flavonoid; to be specific, it is one of the more common flavones. From preliminary research, it is thought to play a role in the human body possibly as an antioxidant, a free radical scavenger, a promoter of carbohydrate metabolism, or an immune...
, supplement extracted from peanuts that also possesses IGF-1 properties. - DrotaverineDrotaverineDrotaverine is an antispasmodic drug, structurally related to papaverine. Drotaverine is a selective inhibitor of phosphodiesterase 4, and has no anticholinergic effects. Drotaverine has been shown to possess dose-dependant analgesic effects in animal models...
, used to alleviate renal colic pain, also to hasten cervical dilatation in labor - RoflumilastRoflumilastRoflumilast is a drug which acts as a selective, long-acting inhibitor of the enzyme PDE-4. It has antiinflammatory effects and is under development as an orally administered drug for the treatment of inflammatory conditions of the lungs such as asthma, and chronic obstructive pulmonary disease...
, indicated for people with severe COPD to prevent symptoms such as coughing and excess mucus from worsening
PDE4 is the major cAMP-metabolizing enzyme found in inflammatory and immune cells. PDE4 inhibitors have proven potential as anti-inflammatory drugs, especially in inflammatory pulmonary diseases such as asthma
Asthma
Asthma is the common chronic inflammatory disease of the airways characterized by variable and recurring symptoms, reversible airflow obstruction, and bronchospasm. Symptoms include wheezing, coughing, chest tightness, and shortness of breath...
, COPD
Chronic obstructive pulmonary disease
Chronic obstructive pulmonary disease , also known as chronic obstructive lung disease , chronic obstructive airway disease , chronic airflow limitation and chronic obstructive respiratory disease , is the co-occurrence of chronic bronchitis and emphysema, a pair of commonly co-existing diseases...
, and rhinitis
Rhinitis
Rhinitis , commonly known as a stuffy nose, is the medical term describing irritation and inflammation of some internal areas of the nose. The primary symptom of rhinitis is nasal dripping. It is caused by chronic or acute inflammation of the mucous membrane of the nose due to viruses, bacteria or...
. They suppress the release of cytokine
Cytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...
s and other inflammatory signals, and inhibit the production of reactive oxygen species. PDE4 inhibitors may have antidepressive effects and have also recently been proposed for use as antipsychotic
Antipsychotic
An antipsychotic is a tranquilizing psychiatric medication primarily used to manage psychosis , particularly in schizophrenia and bipolar disorder. A first generation of antipsychotics, known as typical antipsychotics, was discovered in the 1950s...
s.
On October 26, 2009, The University of Pennsylvania reported that researchers at their institution had discovered a link between elevated levels of PDE4 (and therefore decreased levels of cAMP) in sleep deprived mice. Treatment with a PDE4 inhibitor raised the deficient cAMP levels and restored some functionality to Hippocampus-based memory functions.
PDE5 selective inhibitors
- SildenafilSildenafilSildenafil citrate, sold as Viagra, Revatio and under various other trade names, is a drug used to treat erectile dysfunction and pulmonary arterial hypertension . It was originally developed by British scientists and then brought to market by the US-based pharmaceutical company Pfizer...
, tadalafilTadalafilTadalafil is a PDE5 inhibitor, currently marketed in pill form for treating erectile dysfunction under the name Cialis; and under the name Adcirca for the treatment of pulmonary arterial hypertension...
, vardenafilVardenafilVardenafil is a PDE5 inhibitor used for treating erectile dysfunction that is sold under the trade names Levitra and Staxyn.-History:...
, and the newer udenafilUdenafilUdenafil is a drug used in urology to treat erectile dysfunction. It belongs to a class of drugs called PDE5 inhibitor, which many other erectile dysfunction drugs such as sildenafil, tadalafil, and vardenafil also belong to. It was developed by Dong-A Pharmaceutical and is marketed under the trade...
and avanafilAvanafilAvanafil is a PDE5 inhibitor being developed for erectile dysfunction. Avanafil currently has no trademarked term associated with it but it is being developed by Vivus Inc. It acts by inhibiting a specific phosphodiesterase type 5 enzyme which is found in various body tissues, but primarily in the...
selectively inhibit PDE5, which is cGMP-specific and responsible for the degradation of cGMP in the corpus cavernosumCorpus cavernosumCorpus cavernosum may refer to:* corpus cavernosum clitoridis* corpus cavernosum penis* "corpus cavernosum urethrae" was used for corpus spongiosum in older texts* corpus cavernosum conchae...
. These phosphodiesterase inhibitors are used primarily as remedies for erectile dysfunctionErectile dysfunctionErectile dysfunction is sexual dysfunction characterized by the inability to develop or maintain an erection of the penis during sexual performance....
, as well as having some other medical applications such as treatment of pulmonary hypertensionPulmonary hypertensionIn medicine, pulmonary hypertension is an increase in blood pressure in the pulmonary artery, pulmonary vein, or pulmonary capillaries, together known as the lung vasculature, leading to shortness of breath, dizziness, fainting, and other symptoms, all of which are exacerbated by exertion...
. - DipyridamoleDipyridamoleDipyridamole is a drug that inhibits thrombus formation when given chronically and causes vasodilation when given at high doses over a short time.-Mechanism and effects:...
also inhibits PDE5. This results in added benefit when given together with NONitric oxideNitric oxide, also known as nitrogen monoxide, is a diatomic molecule with chemical formula NO. It is a free radical and is an important intermediate in the chemical industry...
or statinStatinStatins are a class of drugs used to lower cholesterol levels by inhibiting the enzyme HMG-CoA reductase, which plays a central role in the production of cholesterol in the liver. Increased cholesterol levels have been associated with cardiovascular diseases, and statins are therefore used in the...
s. - Claimed newer and more-selective inhibitors are icariinIcariinIcariin is a flavonol, a type of flavonoid. It is the prenyl acetylation of kaempferide 3,7-O-diglucoside. The compound is derived from several species of plants in the Epimedium family, which are commonly known as Horny Goat Weed or Yin Yang Huo...
, an active component of Epimedium grandiflorumEpimedium grandiflorumEpimedium grandiflorum is a species of flowering plant in the barberry family, Berberidaceae, that is native to China, Japan, and Korea. It may have aphrodisiac characteristics due to the presence of icariin and is believed to cause increased sexual activity in goats. It commonly is packed in a...
, and possibly 4-Methylpiperazine and Pyrazolo Pyrimidin-7-1, components of the lichen XanthoparmeliaXanthoparmeliaXanthoparmelia is a genus of lichen belonging to the family Parmeliaceae. Xanthoparmelia is synonymous with Almbornia, Neofuscelia, Chondropsis, Namakwa, Paraparmelia, and Xanthomaculina.This family of lichen is commonly found on the mid-east coast of the United States.The name means 'golden...
scabrosa.
PDE10 selective inhibitors
PapaverinePapaverine
Papaverine is an opium alkaloid antispasmodic drug, used primarily in the treatment of visceral spasm, vasospasm , and occasionally in the treatment of erectile dysfunction...
, an opium
Opium
Opium is the dried latex obtained from the opium poppy . Opium contains up to 12% morphine, an alkaloid, which is frequently processed chemically to produce heroin for the illegal drug trade. The latex also includes codeine and non-narcotic alkaloids such as papaverine, thebaine and noscapine...
alkaloid
Alkaloid
Alkaloids are a group of naturally occurring chemical compounds that contain mostly basic nitrogen atoms. This group also includes some related compounds with neutral and even weakly acidic properties. Also some synthetic compounds of similar structure are attributed to alkaloids...
, has been reported to act as a PDE10 inhibitor.
PDE10A is almost exclusively expressed in the striatum
Striatum
The striatum, also known as the neostriatum or striate nucleus, is a subcortical part of the forebrain. It is the major input station of the basal ganglia system. The striatum, in turn, gets input from the cerebral cortex...
and subsequent increase in cAMP and cGMP after PDE10A inhibition (e.g. by papaverine
Papaverine
Papaverine is an opium alkaloid antispasmodic drug, used primarily in the treatment of visceral spasm, vasospasm , and occasionally in the treatment of erectile dysfunction...
) is "a novel therapeutic avenue in the discovery of antipsychotics".