Ratio of inhibitory potency between phosphodiesterase families

Where it participates (unsigned role)

1. The newly cloned phosphodiesterase PDE9A1 is highly specific for cyclic GMP with a Michaelis constant of approximately 0.07 micromolar, the lowest yet reported for a phosphodiesterase and at least 40 to 170 times lower than that of PDE5 and PDE6 respectively, it shows highest messenger RNA expression in kidney with lower levels in liver, lung and brain, and when expressed in COS-7 cells its activity was not inhibited well by either the nonselective inhibitor 3-isobutyl-1-methylxanthine or the new selective PDE5 inhibitor sildenafil, while the PDE1 and PDE5 inhibitor SCH51866 inhibited it with a half-maximal concentration of 1.55 micromolar.

   Sildenafil → Phosphodiesterase 9A source_derived_draftungraded
   Experimental context and source evidence

   evidence_span

   {"source_cache": "artifacts/sildenafil-research/9624145.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "ea6afcfbb102bf5a407894b06969c9fe245261fa8a1fea8fb92b201d8b24ace2", "start_char": 0, "end_char": 1265, "text_sha256": "ea6afcfbb102bf5a407894b06969c9fe245261fa8a1fea8fb92b201d8b24ace2"}

   experimental_model

   Cloning, expression and kinetic characterisation of a newly identified cyclic nucleotide phosphodiesterase family

   exposure

   Recombinant PDE9A1 against 3-isobutyl-1-methylxanthine, sildenafil and SCH51866

   limitations

   A cloning and characterisation report. The expression survey is messenger RNA rather than protein, and the enzyme is heterologously expressed.

   nutrient_topic

   Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. · Sildenafil

   organism

   Mouse

   plain_language

   There is another enzyme that destroys the same messenger even more avidly, and this drug does not touch it.

   primary_references

   [sil-p9624145] Identification and characterization of a novel family of cyclic nucleotide phosphodiesterases. (1998). https://pubmed.ncbi.nlm.nih.gov/9624145/ DOI: 10.1074/jbc.273.25.15553

   tissue_or_cell_type

   Kidney, liver, lung and brain messenger RNA

   Sildenafil: the enzyme it occupies instead of the substrate, why it cannot start a signal it can only preserve, the organic nitrate interaction that follows from that, the homologous retinal enzyme ten-fold away, and the pulmonary circulation where the same mechanism became a second indication (2026-09-22) · lines 236–247

   AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Cloning, expression and kinetic characterisation of a newly identified cyclic nucleotide phosphodiesterase family · source_derived_draft · unverified_draft

   ### sil-another-cgmp-enzyme-it-misses The newly cloned phosphodiesterase PDE9A1 is highly specific for cyclic GMP with a Michaelis constant of approximately 0.07 micromolar, the lowest yet reported for a phosphodiesterase and at least 40 to 170 times lower than that of PDE5 and PDE6 respectively, it shows highest messenger RNA expression in kidney with lower levels in liver, lung and brain, and when expressed in COS-7 cells its activity was not inhibited well by either the nonselective inhibitor 3-isobutyl-1-methylxanthine or the new selective PDE5 inhibitor sildenafil, while the PDE1 and PDE5 inhibitor SCH51866 inhibited it with a half-maximal concentration of 1.55 micromolar. Condition category: normal nutrient_topic: Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. plain_language: There is another enzyme that destroys the same messenger even more avidly, and this drug does not touch it. organism: Mouse tissue_or_cell_type: Kidney, liver, lung and brain messenger RNA experimental_model: Cloning, expression and kinetic characterisation of a newly identified cyclic nucleotide phosphodiesterase family limitations: A cloning and characterisation report. The expression survey is messenger RNA rather than protein, and the enzyme is heterologously expressed. exposure: Recombinant PDE9A1 against 3-isobutyl-1-methylxanthine, sildenafil and SCH51866 evidence_span: {"source_cache": "artifacts/sildenafil-research/9624145.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "ea6afcfbb102bf5a407894b06969c9fe245261fa8a1fea8fb92b201d8b24ace2", "start_char": 0, "end_char": 1265, "text_sha256": "ea6afcfbb102bf5a407894b06969c9fe245261fa8a1fea8fb92b201d8b24ace2"} [sil-p9624145] Identification and characterization of a novel family of cyclic nucleotide phosphodiesterases. (1998). https://pubmed.ncbi.nlm.nih.gov/9624145/ DOI: 10.1074/jbc.273.25.15553

   Complete structured claim and evidence

2. Image analysis of purified bovine rod phosphodiesterase 6 revealed the three-dimensional dimeric arrangement of the alpha-beta-delta complex and the internal organization of each catalytic subunit into three distinct domains corresponding to the catalytic and two GAF domains, and the three-dimensional molecular organization of human platelet phosphodiesterase type 5 appears highly homologous to that of bovine rod phosphodiesterase 6 as predicted by similarities in their primary sequences.

   Rod PDE6 complex → Phosphodiesterase 5 family source_derived_draftungraded
   Experimental context and source evidence

   evidence_span

   {"source_cache": "artifacts/sildenafil-research/11453687.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "54fdc1cf336b81568055fa21b19ad21600db5bf276dc5dc9e1dcb490cb63de30", "start_char": 0, "end_char": 1312, "text_sha256": "54fdc1cf336b81568055fa21b19ad21600db5bf276dc5dc9e1dcb490cb63de30"}

   experimental_model

   Electron microscopy and single-particle image analysis of purified bovine rod phosphodiesterase 6

   exposure

   Solubilised rod PDE6 depleted of its gamma subunits, with immunolabelling

   limitations

   A structural comparison at 2.8 nanometre resolution rather than atomic detail. The comparison with PDE5 is inferred from sequence similarity and the reconstructed organisation.

   nutrient_topic

   Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. · Sildenafil

   organism

   Cattle

   plain_language

   The retinal enzyme and the target enzyme are built to the same plan, which is why a drug for one reaches the other.

   primary_references

   [sil-p11453687] Molecular organization of bovine rod cGMP-phosphodiesterase 6. (2001). https://pubmed.ncbi.nlm.nih.gov/11453687/ DOI: 10.1006/jmbi.2001.4813

   tissue_or_cell_type

   Retinal rod outer segment

   Sildenafil: the enzyme it occupies instead of the substrate, why it cannot start a signal it can only preserve, the organic nitrate interaction that follows from that, the homologous retinal enzyme ten-fold away, and the pulmonary circulation where the same mechanism became a second indication (2026-09-22) · lines 249–260

   AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Electron microscopy and single-particle image analysis of purified bovine rod phosphodiesterase 6 · source_derived_draft · unverified_draft

   ### sil-pde5-and-pde6-are-built-alike Image analysis of purified bovine rod phosphodiesterase 6 revealed the three-dimensional dimeric arrangement of the alpha-beta-delta complex and the internal organization of each catalytic subunit into three distinct domains corresponding to the catalytic and two GAF domains, and the three-dimensional molecular organization of human platelet phosphodiesterase type 5 appears highly homologous to that of bovine rod phosphodiesterase 6 as predicted by similarities in their primary sequences. Condition category: normal nutrient_topic: Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. plain_language: The retinal enzyme and the target enzyme are built to the same plan, which is why a drug for one reaches the other. organism: Cattle tissue_or_cell_type: Retinal rod outer segment experimental_model: Electron microscopy and single-particle image analysis of purified bovine rod phosphodiesterase 6 limitations: A structural comparison at 2.8 nanometre resolution rather than atomic detail. The comparison with PDE5 is inferred from sequence similarity and the reconstructed organisation. exposure: Solubilised rod PDE6 depleted of its gamma subunits, with immunolabelling evidence_span: {"source_cache": "artifacts/sildenafil-research/11453687.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "54fdc1cf336b81568055fa21b19ad21600db5bf276dc5dc9e1dcb490cb63de30", "start_char": 0, "end_char": 1312, "text_sha256": "54fdc1cf336b81568055fa21b19ad21600db5bf276dc5dc9e1dcb490cb63de30"} [sil-p11453687] Molecular organization of bovine rod cGMP-phosphodiesterase 6. (2001). https://pubmed.ncbi.nlm.nih.gov/11453687/ DOI: 10.1006/jmbi.2001.4813

   Complete structured claim and evidence

3. After site-directed mutagenesis of each of 23 conserved amino acid residues in the catalytic domain, the pattern of changes in inhibitory concentration for sildenafil was most similar to that found for the affinity of cyclic GMP itself, implying similar interactions with the catalytic domain, and residues such as Tyr602, His607, His643 and Asp754 may form important interactions for sildenafil, but because these amino acids are conserved in all mammalian phosphodiesterases the selectivity and potency of the drug is likely to be provided by a nonconserved residue or residues; sildenafil also stimulates cyclic GMP binding to the allosteric sites by interacting at the catalytic site without competing for the allosteric sites themselves.

   Catalytic domain residues Tyr602, His607, His643 and Asp754 of phosphodiesterase type 5 → Sildenafil source_derived_draftungraded
   Experimental context and source evidence

   evidence_span

   {"source_cache": "artifacts/sildenafil-research/10385692.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "9ce2e7f3f2d22246734a6f998124d7a57cc0eded673f321bbc47586fd2ea3bcf", "start_char": 0, "end_char": 1888, "text_sha256": "9ce2e7f3f2d22246734a6f998124d7a57cc0eded673f321bbc47586fd2ea3bcf"}

   experimental_model

   Kinetic and site-directed mutagenesis analysis of inhibitor interaction with the phosphodiesterase type 5 catalytic domain

   exposure

   Sildenafil, UK-122764 and zaprinast against wild-type enzyme and 23 conserved catalytic-domain point mutants

   limitations

   Places the drug at the catalytic site by competition and by a mutant series, and gives the comparison with the natural substrate that makes the affinity meaningful. Recombinant enzyme.

   nutrient_topic

   Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. · Sildenafil

   organism

   Enzyme

   plain_language

   The residues it grips are the same ones every enzyme in the family has, so what makes it selective is something else.

   primary_references

   [sil-p10385692] Inhibition of cyclic GMP-binding cyclic GMP-specific phosphodiesterase (Type 5) by sildenafil and related compounds. (1999). https://pubmed.ncbi.nlm.nih.gov/10385692/ DOI: 10.1124/mol.56.1.124

   tissue_or_cell_type

   Recombinant phosphodiesterase type 5

   Sildenafil: the enzyme it occupies instead of the substrate, why it cannot start a signal it can only preserve, the organic nitrate interaction that follows from that, the homologous retinal enzyme ten-fold away, and the pulmonary circulation where the same mechanism became a second indication (2026-09-22) · lines 171–182

   AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Kinetic and site-directed mutagenesis analysis of inhibitor interaction with the phosphodiesterase type 5 catalytic domain · source_derived_draft · unverified_draft

   ### sil-selectivity-is-not-in-the-conserved-residues After site-directed mutagenesis of each of 23 conserved amino acid residues in the catalytic domain, the pattern of changes in inhibitory concentration for sildenafil was most similar to that found for the affinity of cyclic GMP itself, implying similar interactions with the catalytic domain, and residues such as Tyr602, His607, His643 and Asp754 may form important interactions for sildenafil, but because these amino acids are conserved in all mammalian phosphodiesterases the selectivity and potency of the drug is likely to be provided by a nonconserved residue or residues; sildenafil also stimulates cyclic GMP binding to the allosteric sites by interacting at the catalytic site without competing for the allosteric sites themselves. Condition category: normal nutrient_topic: Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. plain_language: The residues it grips are the same ones every enzyme in the family has, so what makes it selective is something else. organism: Enzyme tissue_or_cell_type: Recombinant phosphodiesterase type 5 experimental_model: Kinetic and site-directed mutagenesis analysis of inhibitor interaction with the phosphodiesterase type 5 catalytic domain limitations: Places the drug at the catalytic site by competition and by a mutant series, and gives the comparison with the natural substrate that makes the affinity meaningful. Recombinant enzyme. exposure: Sildenafil, UK-122764 and zaprinast against wild-type enzyme and 23 conserved catalytic-domain point mutants evidence_span: {"source_cache": "artifacts/sildenafil-research/10385692.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "9ce2e7f3f2d22246734a6f998124d7a57cc0eded673f321bbc47586fd2ea3bcf", "start_char": 0, "end_char": 1888, "text_sha256": "9ce2e7f3f2d22246734a6f998124d7a57cc0eded673f321bbc47586fd2ea3bcf"} [sil-p10385692] Inhibition of cyclic GMP-binding cyclic GMP-specific phosphodiesterase (Type 5) by sildenafil and related compounds. (1999). https://pubmed.ncbi.nlm.nih.gov/10385692/ DOI: 10.1124/mol.56.1.124

   Complete structured claim and evidence

4. Early in development it was noted that besides its major inhibitory effect on the intended target, the vascular-associated PDE5, the drug also exerts a lesser but definite inhibitory effect on the closely related PDE6 located in the retina, and for this reason preclinical evaluation included electroretinography plus postmortem histology and an extended eye examination was incorporated into clinical protocols, with data on the incidence, duration and type of colour vision defects observed at different doses.

   Structural homology between phosphodiesterase type 5 and rod phosphodiesterase 6 → Transient colour vision disturbance and increased light sensitivity source_derived_draftungraded
   Experimental context and source evidence

   evidence_span

   {"source_cache": "artifacts/sildenafil-research/10703120.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "fc004205f7e036cf52e469c5f9941c4f69d216a012ccd8a588052b950c1077e6", "start_char": 0, "end_char": 2146, "text_sha256": "fc004205f7e036cf52e469c5f9941c4f69d216a012ccd8a588052b950c1077e6"}

   experimental_model

   Review of how the ocular safety profile was established from preclinical work through to post-marketing surveillance

   exposure

   Electroretinography and histology in preclinical evaluation, with extended eye examination in clinical protocols and registry surveillance

   limitations

   A methodological review of how the signal was tracked rather than a new measurement. It is useful because it records that the retinal effect was predicted before it was looked for.

   nutrient_topic

   Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. · Sildenafil

   organism

   Human and animal

   plain_language

   The visual effect was not a surprise; the homology between the two enzymes predicted it and the trials were designed to look for it.

   primary_references

   [sil-p10703120] Ocular safety of Viagra, (sildenafil citrate). (1999). https://pubmed.ncbi.nlm.nih.gov/10703120/

   tissue_or_cell_type

   Retina

   Sildenafil: the enzyme it occupies instead of the substrate, why it cannot start a signal it can only preserve, the organic nitrate interaction that follows from that, the homologous retinal enzyme ten-fold away, and the pulmonary circulation where the same mechanism became a second indication (2026-09-22) · lines 496–507

   AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Review of how the ocular safety profile was established from preclinical work through to post-marketing surveillance · source_derived_draft · unverified_draft

   ### sil-the-off-target-was-predicted Early in development it was noted that besides its major inhibitory effect on the intended target, the vascular-associated PDE5, the drug also exerts a lesser but definite inhibitory effect on the closely related PDE6 located in the retina, and for this reason preclinical evaluation included electroretinography plus postmortem histology and an extended eye examination was incorporated into clinical protocols, with data on the incidence, duration and type of colour vision defects observed at different doses. Condition category: normal nutrient_topic: Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. plain_language: The visual effect was not a surprise; the homology between the two enzymes predicted it and the trials were designed to look for it. organism: Human and animal tissue_or_cell_type: Retina experimental_model: Review of how the ocular safety profile was established from preclinical work through to post-marketing surveillance limitations: A methodological review of how the signal was tracked rather than a new measurement. It is useful because it records that the retinal effect was predicted before it was looked for. exposure: Electroretinography and histology in preclinical evaluation, with extended eye examination in clinical protocols and registry surveillance evidence_span: {"source_cache": "artifacts/sildenafil-research/10703120.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "fc004205f7e036cf52e469c5f9941c4f69d216a012ccd8a588052b950c1077e6", "start_char": 0, "end_char": 2146, "text_sha256": "fc004205f7e036cf52e469c5f9941c4f69d216a012ccd8a588052b950c1077e6"} [sil-p10703120] Ocular safety of Viagra, (sildenafil citrate). (1999). https://pubmed.ncbi.nlm.nih.gov/10703120/

   Complete structured claim and evidence

5. Sildenafil inhibited PDE5 from human corpus cavernosum with a geometric mean half-maximal inhibitory concentration of 3.5 nanomolar and was approximately 240-fold more potent than zaprinast, values for inhibition of PDE1 to PDE4 were 80 to more than 8500 times greater than that for PDE5, and the value for PDE6 at 33 nanomolar was approximately 9-fold greater.

   Sildenafil → Phosphodiesterase 5 family source_derived_draftungraded
   Experimental context and source evidence

   evidence_span

   {"source_cache": "artifacts/sildenafil-research/9598563.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "860e09237bbae4ec5bb65a640186902908ccb9c6ec502b504a1ecddbb33810a2", "start_char": 0, "end_char": 1755, "text_sha256": "860e09237bbae4ec5bb65a640186902908ccb9c6ec502b504a1ecddbb33810a2"}

   experimental_model

   Isolated human corpus cavernosum strips with electrical field stimulation, and phosphodiesterase assays across families 1 to 6

   exposure

   Sildenafil against PDE1 to PDE5 prepared from human tissues and PDE6 from bovine retina, with zaprinast as comparator

   limitations

   Measures the full selectivity series in one laboratory using the same method, which is what makes the ratios comparable. The PDE6 preparation is bovine retina rather than human.

   nutrient_topic

   Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. · Sildenafil

   organism

   Human and bovine enzyme

   plain_language

   It is hundreds to thousands of times more selective against most of the enzyme family, and only about nine times against the one in the retina.

   primary_references

   [sil-p9598563] Effects of sildenafil on the relaxation of human corpus cavernosum tissue in vitro and on the activities of cyclic nucleotide phosphodiesterase isozymes. (1998). https://pubmed.ncbi.nlm.nih.gov/9598563/ DOI: 10.1016/s0022-5347(01)63299-3

   tissue_or_cell_type

   Corpus cavernosum and bovine retina

   Sildenafil: the enzyme it occupies instead of the substrate, why it cannot start a signal it can only preserve, the organic nitrate interaction that follows from that, the homologous retinal enzyme ten-fold away, and the pulmonary circulation where the same mechanism became a second indication (2026-09-22) · lines 132–143

   AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Isolated human corpus cavernosum strips with electrical field stimulation, and phosphodiesterase assays across families 1 to 6 · source_derived_draft · unverified_draft

   ### sil-the-selectivity-series Sildenafil inhibited PDE5 from human corpus cavernosum with a geometric mean half-maximal inhibitory concentration of 3.5 nanomolar and was approximately 240-fold more potent than zaprinast, values for inhibition of PDE1 to PDE4 were 80 to more than 8500 times greater than that for PDE5, and the value for PDE6 at 33 nanomolar was approximately 9-fold greater. Condition category: normal nutrient_topic: Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. plain_language: It is hundreds to thousands of times more selective against most of the enzyme family, and only about nine times against the one in the retina. organism: Human and bovine enzyme tissue_or_cell_type: Corpus cavernosum and bovine retina experimental_model: Isolated human corpus cavernosum strips with electrical field stimulation, and phosphodiesterase assays across families 1 to 6 limitations: Measures the full selectivity series in one laboratory using the same method, which is what makes the ratios comparable. The PDE6 preparation is bovine retina rather than human. exposure: Sildenafil against PDE1 to PDE5 prepared from human tissues and PDE6 from bovine retina, with zaprinast as comparator evidence_span: {"source_cache": "artifacts/sildenafil-research/9598563.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "860e09237bbae4ec5bb65a640186902908ccb9c6ec502b504a1ecddbb33810a2", "start_char": 0, "end_char": 1755, "text_sha256": "860e09237bbae4ec5bb65a640186902908ccb9c6ec502b504a1ecddbb33810a2"} [sil-p9598563] Effects of sildenafil on the relaxation of human corpus cavernosum tissue in vitro and on the activities of cyclic nucleotide phosphodiesterase isozymes. (1998). https://pubmed.ncbi.nlm.nih.gov/9598563/ DOI: 10.1016/s0022-5347(01)63299-3

   Complete structured claim and evidence