Phosphodiesterase inhibitor

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Phosphodiesterase-5

A phosphodiesterase inhibitor is a drug that blocks one or more of the five subtypes of the enzyme phosphodiesterase (PDE), thereby preventing the inactivation of the intracellular second messengers, cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) by the respective PDE subtype(s). The ubiquitous presence of this enzyme means that non-specific inhibitors have a wide range of actions, the actions in the heart, and lungs being some of the first to find a therapeutic use.

Contents

History

The different forms or subtypes of phosphodiesterase were initially isolated from rat brains in the early 1970s [1] [2] and were soon afterward shown to be selectively inhibited in the brain and in other tissues by a variety of drugs. [3] [4] The potential for selective phosphodiesterase inhibitors as therapeutic agents was predicted as early as 1977 by Weiss and Hait. [5] This prediction meanwhile has proved to be true in a variety of fields.

Classification

Nonselective PDE inhibitors

Methylated xanthines and derivatives: [6]

Methylated xanthines act as both

  1. competitive nonselective phosphodiesterase inhibitors, [6] which raise intracellular cAMP, activate PKA, inhibit TNF-alpha [7] [8] and leukotriene [9] synthesis, and reduce inflammation and innate immunity [9] and
  2. nonselective adenosine receptor antagonists [10]

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. [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23]

PDE2 selective inhibitors

PDE3 selective inhibitors

PDE3 is sometimes referred to as cGMP-inhibited phosphodiesterase.

PDE4 selective inhibitors

PDE4 inhibitors PDE4-inhibiting thalidomide analogs.svg
PDE4 inhibitors

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 cytokines and other inflammatory signals, and inhibit the production of reactive oxygen species. PDE4 inhibitors may have antidepressive effects [28] and have also been proposed for use as antipsychotics. [29] [30]

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. [31]

PDE5 selective inhibitors

PDE7 selective inhibitors

Recent studies have shown quinazoline type PDE7 inhibitor to be potent anti-inflammatory and neuroprotective agents. [32]

PDE9 selective inhibitors

Paraxanthine, the main metabolite of caffeine (84% in humans), [33] is another cGMP-specific phosphodiesterase inhibitor which inhibits PDE9, a cGMP preferring phosphodiesterase. [34] [35] PDE9 is expressed as high as PDE5 in the corpus cavernosum. [36]

PDE10 selective inhibitors

Papaverine, an opium alkaloid, has been reported to act as a PDE10 inhibitor. [37] [38] [39] 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". [40]

Related Research Articles

<span class="mw-page-title-main">Xanthine</span> Chemical compound

Xanthine is a purine base found in most human body tissues and fluids, as well as in other organisms. Several stimulants are derived from xanthine, including caffeine, theophylline, and theobromine.

<span class="mw-page-title-main">Theophylline</span> Drug used to treat respiratory diseases

Theophylline, also known as 1,3-dimethylxanthine, is a drug that inhibits phosphodiesterase and blocks adenosine receptors. It is used to treat chronic obstructive pulmonary disease (COPD) and asthma. Its pharmacology is similar to other methylxanthine drugs. Trace amounts of theophylline are naturally present in tea, coffee, chocolate, yerba maté, guarana, and kola nut.

<span class="mw-page-title-main">Phosphodiesterase</span> Class of enzymes

A phosphodiesterase (PDE) is an enzyme that breaks a phosphodiester bond. Usually, phosphodiesterase refers to cyclic nucleotide phosphodiesterases, which have great clinical significance and are described below. However, there are many other families of phosphodiesterases, including phospholipases C and D, autotaxin, sphingomyelin phosphodiesterase, DNases, RNases, and restriction endonucleases, as well as numerous less-well-characterized small-molecule phosphodiesterases.

cGMP-specific phosphodiesterase type 5 Mammalian protein found in Homo sapiens

Cyclic guanosine monophosphate-specific phosphodiesterase type 5 is an enzyme from the phosphodiesterase class. It is found in various tissues, most prominently the corpus cavernosum and the retina. It has also been recently discovered to play a vital role in the cardiovascular system.

<span class="mw-page-title-main">Aminophylline</span> Chemical compound

Aminophylline 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.

<span class="mw-page-title-main">Paraxanthine</span> Chemical compound

Paraxanthine, also known as 1,7-dimethylxanthine, is a metabolite of theophylline and theobromine, two well-known stimulants found in coffee, tea, and chocolate mainly in the form of caffeine. It is a member of the xanthine family of alkaloids, which includes theophylline, theobromine and caffeine.

<span class="mw-page-title-main">Rolipram</span> Chemical compound

Rolipram is a selective phosphodiesterase-4 inhibitor discovered and developed by Schering AG as a potential antidepressant drug in the early 1990s. It served as a prototype molecule for several companies' drug discovery and development efforts. Rolipram was discontinued after clinical trials showed that its therapeutic window was too narrow; it could not be dosed at high enough levels to be effective without causing significant gastrointestinal side effects.

<span class="mw-page-title-main">Phosphodiesterase 3</span> Class of enzymes

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. Most of the PDE families are composed of more than one gene. PDE3 is clinically significant because of its role in regulating heart muscle, vascular smooth muscle and platelet aggregation. PDE3 inhibitors have been developed as pharmaceuticals, but their use is limited by arrhythmic effects and they can increase mortality in some applications.

<span class="mw-page-title-main">Phosphodiesterase 2</span> Class of enzymes

The PDE2 enzyme is one of 21 different phosphodiesterases (PDE) found in mammals. These different PDEs can be subdivided to 11 families. The different PDEs of the same family are functionally related despite the fact that their amino acid sequences show considerable divergence. The PDEs have different substrate specificities. Some are cAMP selective hydrolases, others are cGMP selective hydrolases and the rest can hydrolyse both cAMP and cGMP.

<span class="mw-page-title-main">IBMX</span> Chemical compound

IBMX (3-isobutyl-1-methylxanthine), like other methylxanthine derivatives, is both a:

  1. competitive non-selective phosphodiesterase inhibitor which raises intracellular cAMP, activates PKA, inhibits TNFα and leukotriene synthesis, and reduces inflammation and innate immunity, and
  2. nonselective adenosine receptor antagonist.
<span class="mw-page-title-main">Dipropylcyclopentylxanthine</span> Chemical compound

8-Cyclopentyl-1,3-dipropylxanthine (DPCPX, PD-116,948) is a drug which acts as a potent and selective antagonist for the adenosine A1 receptor. It has high selectivity for A1 over other adenosine receptor subtypes, but as with other xanthine derivatives DPCPX also acts as a phosphodiesterase inhibitor, and is almost as potent as rolipram at inhibiting PDE4. It has been used to study the function of the adenosine A1 receptor in animals, which has been found to be involved in several important functions such as regulation of breathing and activity in various regions of the brain, and DPCPX has also been shown to produce behavioural effects such as increasing the hallucinogen-appropriate responding produced by the 5-HT2A agonist DOI, and the dopamine release induced by MDMA, as well as having interactions with a range of anticonvulsant drugs.

<span class="mw-page-title-main">PDE4A</span> Protein-coding gene in the species Homo sapiens

cAMP-specific 3',5'-cyclic phosphodiesterase 4A is an enzyme that in humans is encoded by the PDE4A gene.

<span class="mw-page-title-main">PDE4B</span> Protein-coding gene in the species Homo sapiens

cAMP-specific 3',5'-cyclic phosphodiesterase 4B is an enzyme that in humans is encoded by the PDE4B gene.

<span class="mw-page-title-main">Etazolate</span> Chemical compound

Etazolate (SQ-20,009, EHT-0202) is an anxiolytic drug which is a pyrazolopyridine derivative and has unique pharmacological properties. It acts as a positive allosteric modulator of the GABAA receptor at the barbiturate binding site, as an adenosine antagonist of the A1 and A2 subtypes, and as a phosphodiesterase inhibitor selective for the PDE4 isoform. It is currently in clinical trials for the treatment of Alzheimer's disease.

<span class="mw-page-title-main">Phosphodiesterase-4 inhibitor</span> Class of chemical compounds

A phosphodiesterase-4 inhibitor, commonly referred to as a PDE4 inhibitor, is a drug used to block the degradative action of phosphodiesterase 4 (PDE4) on cyclic adenosine monophosphate (cAMP). It is a member of the larger family of PDE inhibitors. The PDE4 family of enzymes are the most prevalent PDE in immune cells. They are predominantly responsible for hydrolyzing cAMP within both immune cells and cells in the central nervous system.

<span class="mw-page-title-main">Piclamilast</span> Chemical compound

Piclamilast, 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. It is a second generation compound that exhibits structural functionalities of the PDE4 inhibitors cilomilast and roflumilast. The structure for piclamilast was first elucidated in a 1995 European patent application. The earliest mention of the name "piclamilast" was used in a 1997 publication.

<span class="mw-page-title-main">Cartazolate</span> Chemical compound

Cartazolate (SQ-65,396) is a drug of the pyrazolopyridine class. It acts as a GABAA receptor positive allosteric modulator at the barbiturate binding site of the complex and has anxiolytic effects in animals. It is also known to act as an adenosine antagonist at the A1 and A2 subtypes and as a phosphodiesterase inhibitor. Cartazolate was tested in human clinical trials and was found to be efficacious for anxiety but was never marketed. It was developed by a team at E.R. Squibb and Sons in the 1970s.

<span class="mw-page-title-main">CGS-15943</span> Chemical compound

CGS-15943 is a drug which acts as a potent and reasonably selective antagonist for the adenosine receptors A1 and A2A, having a Ki of 3.3nM at A2A and 21nM at A1. It was one of the first adenosine receptor antagonists discovered that is not a xanthine derivative, instead being a triazoloquinazoline. Consequently, CGS-15943 has the advantage over most xanthine derivatives that it is not a phosphodiesterase inhibitor, and so has more a specific pharmacological effects profile. It produces similar effects to caffeine in animal studies, though with higher potency.

<span class="mw-page-title-main">8-Phenyltheophylline</span> Chemical compound

8-Phenyltheophylline (8-phenyl-1,3-dimethylxanthine, 8-PT) is a drug derived from the xanthine family which acts as a potent and selective antagonist for the adenosine receptors A1 and A2A, but unlike other xanthine derivatives has virtually no activity as a phosphodiesterase inhibitor. It has stimulant effects in animals with similar potency to caffeine. Coincidentally 8-phenyltheophylline has also been found to be a potent and selective inhibitor of the liver enzyme CYP1A2 which makes it likely to cause interactions with other drugs which are normally metabolised by CYP1A2.

Phosphodiesterases (PDEs) are a superfamily of enzymes. This superfamily is further classified into 11 families, PDE1 - PDE11, on the basis of regulatory properties, amino acid sequences, substrate specificities, pharmacological properties and tissue distribution. Their function is to degrade intracellular second messengers such as cyclic adenine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) which leads to several biological processes like effect on intracellular calcium level by the Ca2+ pathway.

References

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  35. ↑ Orrú, Marco; Guitart, Xavier; Karcz-Kubicha, Marzena; Solinas, Marcello; Justinova, Zuzana; Barodia, Sandeep Kumar; Zanoveli, Janaina; Cortes, Antoni; Lluis, Carme; Casado, Vicent; Moeller, F. Gerard (April 2013). "Psychostimulant pharmacological profile of paraxanthine, the main metabolite of caffeine in humans". Neuropharmacology. 67C: 476–484. doi:10.1016/j.neuropharm.2012.11.029. ISSN   0028-3908. PMC   3562388 . PMID   23261866.
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  37. ↑ Weber M, Breier M, Ko D, Thangaraj N, Marzan DE, Swerdlow NR (May 2009). "Evaluating the antipsychotic profile of the preferential PDE10A inhibitor, papaverine". Psychopharmacology. 203 (4): 723–35. doi:10.1007/s00213-008-1419-x. PMC   2748940 . PMID   19066855.
  38. ↑ Inhibitory Mechanism of Papaverine on Carbachol-Induced Contraction in Bovine Trachea; Takeharu Kaneda1,*, Yukako Takeuchi1, Hirozumi Matsui1, Kazumasa Shimizu1, Norimoto Urakawa1,and Shinjiro Nakajyo, Division of Veterinary Pharmacology, Nippon Veterinary and Animal Science University; http://www.jstage.jst.go.jp/article/jphs/98/3/275/_pdf%5B%5D
  39. ↑ Pöch, G.; Kukovetz, W.R. (1971). "Papaverine - induced inhibition of phosphodiesterase activity in various mammalian tissues". Life Sciences. 10 (3): 133–144. doi:10.1016/0024-3205(71)90086-5. PMID   4325052.
  40. ↑ Effects of phosphodiesterase 10 inhibition on striatal cyclic AMP and peripheral physiology in rats; An Torremans, Abdellah Ahnaou, An Van Hemelrijck, Roel Straetemans, Helena Geys, Greet Vanhoof, Theo F. Meert, and Wilhelmus H. Drinkenburg; "Archived copy" (PDF). Archived (PDF) from the original on 2011-10-07. Retrieved 2011-08-27.{{cite web}}: CS1 maint: archived copy as title (link)
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