PDE5: A target for erectile dysfunction

Mr. L. Jayashankar

Phosphodiesterases are enzymes that catalyze the degradation of the cyclic nucleotides, cyclic AMP and cyclic GMP, to the corresponding 5’ nucleotide monophosphates. Ten different phosphodiesterase families have been described to date.

These enzymes exist as homodimers and there is structural similarity between the different families. However, they differ in several respects like selectivity for cyclic nucleotides, sensitivity for inhibitors and activators, physiological roles and tissue distribution.

Physiological Properties

Physiological activity of the Enzyme

A phosphodiesterase is an enzyme that catalyzes the hydrolysis of phosphodiester bonds, for instance a bond in a molecule of cyclic AMP or cyclic GMP (Figure 1) . It plays a role in signal transduction by regulating the intracellular concentration of cyclic nucleotides. This phosphodiesterase catalyzes the specific hydrolysis of cGMP to 5'-GMP. Human phosphodiesterase 5 is responsible for the degradation of cyclic GMP in the corpus cavernosum.

Other Physiological Functions

PDE5 inhibitors have been shown to reduce blood pressure in patients with pulmonary hypertension, and in animal models, have potential for use in the treatment of stroke.

Catalytic Activity

Catalytic activity of the PDE5 enzyme on the reaction of Guanosine 3', 5'-cyclic phosphate + H ₂ O = guanosine 5'-phosphate shown in Figure 3.

Tissue Specificity

Phosphodiesterase5 (PDE5) is found in high concentration in smooth muscle cells of the corpora cavernosa. It is also expressed in various other tissues (Table 1) , such as the arterial vasculature, including pulmonary and coronary arteries, venous vasculature, skeletal muscles, visceral and tracheo-bronchial muscles, placenta, skeletal muscle, pancreas, platelets and to a much lesser extent in brain and liver.

Catalytic Domain

Composed of a C-terminal catalytic domain containing two putative divalent metal sites and an N-terminal regulatory domain that contains two homologous allosteric cGMP-binding regions, A and B.

Enzymes in Phosphodiesterase Family

It belongs to the cyclic nucleotide phosphodiesterase family and the other Phosphodiesterases enzymes are shown in Table 1.

Table 1. Phosphodiesterases: Localization and Role

3D Crystal structure details of PDE5

Crystal structures of Human Phosphodiesterase 5 complexed with three different inhibitors are available in the protein data bank www.rcsb.org

Crystal Structure Of Human Phosphodiesterase 5 Complexed With Sildenafil (Viagra) – 1UDT ( Resolution 2.30) Crystal Structure Of Human Phosphodiesterase 5 Complexed With Tadalafil (Cialis) – 1UDU ( Resolution 2.83) Crystal Structure Of Human Phosphodiesterase 5 Complexed With Vardenafil (Levitra) - 1UHO ( Resolution 2.50)

Figure 2: 3D Crystal Structure of PDE 5 Complex structure (1UDT)

Pathological Importance

Phosphodiesterase 5 is responsible for the degradation of cGMP in the smooth muscle cells lining the blood vessels supplying the corpus cavernosum of the penis, which leads to erectile dysfunction.

Erectile Dysfunction

Erectile dysfunction is defined as the persistent inability to attain or maintain penile erection adequate for sexual intercourse. This condition, to some degree, affects more than one half of all men over the age of 40, including 30 million men in the US and more than 150 million men worldwide. While it was thought for years that most cases of ED were of psychogenic origin, current statistics suggest that more than half of the cases may be caused by organic syndromes including,

Ø Adverse drug reactions (diuretics and anti-hypertensives, antidepressants, antipsychotics, anticonvulsants, and sedative/hypnotics),

Ø Chronic disease (mainly diabetes but also heart, liver, and kidney disease)

Ø Endocrine disorders (altered testosterone or prolactin levels)

Ø Vascular disease (atherosclerosis)

Ø Primary neurologic disorders (spinal cord injury, multiple sclerosis, Alzheimer's disease, parkinsonism)

Ø Surgical procedures that damage parasympathetic nerve fibers including prostatectomy, cystectomy, and kidney transplantation.

Erectile tissue consists of cavernous, venous sinusoids that are normally empty but dilate substantially when blood pressure increases, resulting in erection. The organic or physiological mechanisms of penile erection have been elucidated and appear to involve two main phases.

1. The first is an autonomic nervous system component and involves stimulation of the cavernous nerve that induces changes in blood flow resulting in full erection.
2. The second phase involves motor-mediated stimulation of the pudendal nerve, which causes the bulbocavernosus and ischiocavernosus muscles to contract, thereby occluding venous outflow.

These mechanisms combine then to simultaneously dilate the arteries and restrict the veins, allowing blood to build up under pressure to establish and maintain the erection characteristic of this tissue. While the physiologic mechanisms involved in producing an erection are well understood, the psychogenic factors involved in male sexual stimulation (visual, auditory, and sensual stimuli) and the relationship between the physiologic and psychogenic processes remains unclear.

Cyclic Guanosine Monophosphate (cGMP)

cGMP is a cyclic nucleotide (a second messenger) derived from guanosine triphosphate (GTP). cGMP acts as a second messenger much like cyclic AMP (Figure 3), most notably by activating intracellular protein kinases in response to the binding of membrane-impermeable peptide hormones to the external cell surface.

Figure 3: Chemical pathways for the synthesis and degradation of cAMP. cAMP is synthesized from ATP by the enzyme adenylyl cyclase with the release of pyrophosphate and hydrolyzed into 5' -AMP by the enzyme phosphodiesterase. Both reactions require Mg ²⁺ . Analogous reactions underlie the synthesis and degradation of cGMP (not shown).

Synthesis

cGMP synthesis is catalyzed by guanylate cyclase (GC) which converts GTP to cGMP. Peptide hormones such as the natriuretic factors activate membrane-bound GC, while nitric oxide typically stimulates cGMP synthesis in soluble GC.

Effects

cGMP relaxes smooth muscle tissues. In blood vessels, relaxation of vascular smooth muscles leads to vasodilation and increased blood flow. It also regulates ion channel conductance, glycogenolysis, and cellular apoptosis. 

Figure 4: Pharmacology of PDE 5 inhibitors

Degradation

Cyclic nucleotide phosphodiesterases (PDE 1-6) degrade cGMP by hydrolyzing cGMP into 5'-GMP (Figure 4).

Current Status of This Target

Human Phosphodiesterase inhibitor

A phosphodiesterase inhibitor is a molecule that blocks one or more of the five subtypes of the enzyme phosphodiesterase (PDE), preventing the inactivation of the intracellular second messengers, cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Relatively non-selective phosphodiesterase inhibitors include the minor stimulant caffeine and the bronchodilator Theophylline. Sildenafil, Tadalafil and Vardenafil are selective inhibitors of type V phosphodiesterase (PDE V) (Table 2) , which is cGMP-specific and responsible for the degradation of cGMP in the corpus cavernosum. These phosphodiesterase inhibitors are used as remedies for erectile dysfunction. Enoximone, which inhibits PDE IV, and Milrinone (Table 3) , which inhibits PDE IIIc, are useful for short-term treatment of cardiac failure. Clinically these molecules mimic sympathetic stimulation and increase cardiac output.

Table 2: Tissue Distribution of Different PDE Isoforms and Selectivity of Sildenafil, Vardenafil, and Tadalafil

Human Phosphodiesterase 5 inhibitor

A phosphodiesterase type 5 inhibitor, often shortened to PDE5 inhibitor, is a molecule used to block the degradative action of phosphodiesterase type 5 on cyclic GMP in the smooth muscle cells lining the blood vessels supplying the corpus cavernosum of the penis. These molecules are used in the treatment of erectile dysfunction, and were the first effective oral treatment available for the condition.

Table 3: Classification and Selected Properties of Cyclic Nucleotide Phosphodiesterases

Mode of action

Part of the physiological process of erection involves the release of nitric oxide (NO) in vasculature of the corpus cavernosum. NO activates the enzyme guanylate cyclase, which results in increased levels of cyclic guanosine monophosphate (cGMP), leading to smooth muscle relaxation in blood vessels supplying the corpus cavernosum, resulting in increased inflow of blood and an erection. PDE5 inhibitors inhibit the degradation of cGMP by phosphodiesterase type 5 (PDE5), increasing blood flow to the penis during sexual stimulation. This mode of action means that PDE5 inhibitors are ineffective without sexual stimulation.

Clinical Update

Over the past several years, many males have largely avoided the topic of erectile dysfunction. However, with the extensive media coverage and aggressive advertising campaign for Sildenafil (Viagara), the reticence surrounding this condition has been dramatically lessened. In fact, the introduction of this agent, a phosphodiesterase type 5 inhibitor, transformed the clinical landscape of erectile dysfunction, empowering many men to seek treatment for this disorder.

Indications

PDE5 inhibitors are clinically indicated for the treatment of erectile dysfunction. Sildenafil, the prototypical PDE5 inhibitor, was originally discovered during the search of a novel treatment for angina. Recent studies are exploring its use as a treatment for pulmonary hypertension.

Contraindications

PDE5 inhibitors are contraindicated in those taking nitrate medications. They are also contraindicated in men for whom sexual intercourse is inadvisable due to cardiovascular risk factors.

Adverse drug reactions

The occurrence of adverse drug reactions (ADRs) with PDE5 inhibitors appears to be dose related. Headache is a very common ADR, occurring in >10% of patients. Other common ADRs include: dizziness, flushing, dyspepsia, nasal congestion or rhinitis.

Sildenafil

Sildenafil citrate, sold under the name Viagra, a potent and selective PDE-5 inhibitor, which is the first drug in this class to be approved for treatment of ED. More than 10 million men worldwide have been treated with this drug. The pills are blue with the words "Pfizer" on one side and "VGR xx" (with xx being either 25, 50 or 100 mg as the dose) on the other.

Chemistry

Chemical name: 1-[4-ethoxy- 3-(6,7-dihydro- 1-methyl- 7-oxo- 3-propyl- 1 H -pyrazolo [4, 3- d ] pyrimidin-5-yl) phenylsulfonyl]- 4-methylpiperazine citrate

Chemical formula: C ₂₂ H ₃₀ N ₆ O ₄ S·C ₆ H ₈ O ₇

Molecular weight: 666.7 g/mol 

Molecular structure (as the base, not the citrate salt):

Mechanism of action

Sildenafil is a potent and selective inhibitor of cGMP specific phosphodiesterase type 5 (PDE5) that is responsible for degradation of cGMP in the corpus cavernosum. This means that, with Viagra on board, normal sexual stimulation leads to increased levels of cGMP in the corpus cavernosum, which leads to better erections. Without sexual stimulation and no activation of the NO/cGMP system, Viagra should not cause an erection. 

Other drugs that operate by the same mechanism include Cialis and Levitra.  Viagra is metabolised by hepatic enzymes and excreted by both the liver and kidneys. If taken with a high fat meal, there may be a delay in absorption of Viagra and the net effect might be muted slightly as the plasma concentration will be lowered.  Some reports have claimed that Viagra causes enhanced sexual pleasure for women by increasing blood flow to the sexual organs.

Contraindications and side effects

Amongst Viagra's serious adverse effects are: priapism, severe hypotension, myocardial infarction, ventricular arrhythmias, sudden death, stroke and increased intraocular pressure. Common side effects include sneezing, headache, flushing, dyspepsia, prolonged erections, palpitations and photophobia. Visual changes including blurring of vision and a curious bluish tinge have also been reported.

Tadalafil

Cialis® (generic name, Tadalafil) is the brand name of a drug used to treat male erectile dysfunction (impotence), developed by the biotech firm ICOS and marketed worldwide by Eli Lilly. The tablets are yellow, oval-shaped and has FDA approval.

Action and Side Effects

Cialis's main selling points are that it works for up to 36 hours after being swallowed and that it can be taken with or without food (Viagra works for some 4 hours). It has the same mode of action as Sildenafil (Viagra), and Vardenafil (Levitra).

Common side effects with Cialis include headache, upset stomach, back pain, and muscle aches, the last two usually coming 12–24 hours after taking the drug. These side effects usually go away after a few hours, though back pain and muscle aches may take as long as 48 hours. Men taking nitrates or alpha-blockers should not take Cialis because it could cause blood pressure problems. Some of the side effects of the drug include backache, stomachache, muscle aches, or headaches. The company advises that in the rare event that an erection lasts for more than four hours (a condition called priapism), the man should seek emergency medical attention.

Vardenafil

Vardenafil (Levitra) is a PDE5 inhibitor used in the treatment of erectile dysfunction. It can assist men with this disorder in achieving and maintaining an erection during sexual activity. As a PDE5 inhibitor, Vardenafil is closely related in both function and marketing to Sildenafil and Tadalafil; it has a relatively short effective time, comparable to Sildenafil.

References

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5. Helmut Haning, 1 Ulrich Niewo ¨ Hner 1, and Erwin Bischoff , Phosphodiesterase Type 5 (PDE5) Inhibitors 1 Bayer AG Pharmaceutical Business Group, Medicinal Chemistry, D-42096 Wuppertal, Germany 2 Bayer AG Pharmaceutical Business Group, Institute of Cardiovascular Research II, P.O. Box 101709, D-42096, Wuppertal, Germany.
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9. http://en.wikipedia.org/wiki/PDE5_inhibitor
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About Authors :

Mr. L. Jayashankar *

*Author for Correspondence

Research Scholar(Pharmaceutical chemistry), Department of Chemistry, Acharya Nagarjuna University , Guntur .

Prof. B. Syama Sundar

Professor, Department of Chemistry, Acharya Nagarjuna University , Guntur

Goutami Mohanty

Research Associate, GVK Bio Sciences, Informatics Division,Hyderabad

Guru Prasad Mohanty

Research Associate, GVK Bio Sciences, Informatics Division, Hyderabad