Identification of Amino Acid Residues Responsible for the Selectivity of Tadalafil Binding to Two Closely Related Phosphodiesterases, PDE5 and PDE6

Cahill, Karyn B.; Quade, Johnathon H.; Carleton, Karen L.; Cote, Rick H.

doi:10.1074/jbc.m112.389189

Cited by 34 publications

(26 citation statements)

References 37 publications

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“…The inhibitory activity on PDE6 is another concern because it disrupts the cGMP signalling pathway used in retinal transduction and this is avoided in the highly selective PDE5 inhibitor, tadalafil [19]. The inhibition by these compounds on PDE6 suggests that 1, 3 and 4 had weak actions compared with the corresponding actions on PDE5 and accords with the 10‐fold selectivity of sildenafil [20].…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Curcumin analogues inhibit phosphodiesterase-5 and dilate rat pulmonary arteries

Kruangtip

Chootip

Temkitthawon

et al. 2015

Journal of Pharmacy and Pharmacology

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Section: Discussionmentioning

confidence: 99%

“…Demethylation of 1 gave the more polar analogue 4 resulting in a twofold lower inhibitory activity while removing both methoxyl groups yielded compound 3, which produced a fourfold reduction in activity. It might be possible that these metapositions need these bulky substituents for binding to the active site [19]…”

Section: Discussionmentioning

confidence: 99%

Curcumin analogues inhibit phosphodiesterase-5 and dilate rat pulmonary arteries

Kruangtip

Chootip

Temkitthawon

et al. 2015

Journal of Pharmacy and Pharmacology

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“…[13][14][15] Figure 4 summarizes the concentration-inhibition curves for tadalafil obtained from 3 in vitro studies, [13][14][15] in which the molar concentration of the drug was converted to mass concentration. When referring to the concentration-inhibition curves in Figure 4, the unbound postdose concentrations of tadalafil observed in our children (gray shaded region, corresponding to 5.9-146 nmol/L) were greater than the reported IC 50 values and seem to be clinically acceptable.…”

Section: Discussionmentioning

confidence: 99%

“…The unbound concentrations found in routinely treated children with PAH were compared with the concentration-inhibition curves and/or IC 50 value for tadalafil against PDE5, which were obtained from 3 recent in vitro studies. [13][14][15] …”

Section: Introductionmentioning

confidence: 99%

Plasma Concentrations of Tadalafil in Children With Pulmonary Arterial Hypertension

Kohno¹,

Ichida²,

Hirono³

et al. 2014

Therapeutic Drug Monitoring

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We demonstrated variability in the total and unbound plasma concentrations of tadalafil in children. However, all children received the empirical doses of the drug; a mean dose of 0.97 mg·kg-1·d-1 showed sufficient unbound concentrations needed for half-maximal inhibition of human phosphodiesterase-5 in vitro. These observations may provide information for the proper use of tadalafil to treat children with PAH.

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“…Progress in investigating the mechanisms of PDE6 mutations has been slow due to a lack of a heterologous expression system [16–20]. Chimeras between cone PDE6C and the related cGMP-specific PDE5 (PDE5/6) or chimeric PDE5/6C catalytic domains have been employed to overcome this limitation [17, 19, 21].…”

Section: Introductionmentioning

confidence: 99%

Mechanisms of mutant PDE6 proteins underlying retinal diseases

Gopalakrishna

Boyd

Artemyev

2017

Cellular Signalling

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Mutations in PDE6 genes encoding the effector enzymes in rods and cones underlie severe retinal diseases including retinitis pigmentosa (RP), autosomal dominant congenital stationary night blindness (adCSNB), and achromatopsia (ACHM). Here we examined a spectrum of pathogenic missense mutations in PDE6 using the system based on co-expression of cone PDE6C with its specialized chaperone AIPL1 and the regulatory Pγ subunit as a potent co-chaperone. We uncovered two mechanisms of PDE6C mutations underlying ACHM: (a) folding defects leading to expression of catalytically inactive proteins and (b) markedly diminished ability of Pγ to co-chaperone mutant PDE6C proteins thereby dramatically reducing the levels of functional enzyme. The mechanism of the Rambusch adCSNB associated with the H258N substitution in PDE6B was probed through the analysis of the model mutant PDE6C-H262N. We identified two interrelated deficits of PDE6C-H262N: disruption of the inhibitory interaction of Pγ with mutant PDE6C that markedly reduced the ability of Pγ to augment the enzyme folding. Thus, we conclude that the Rambusch adCSNB is triggered by low levels of the constitutively active PDE6. Finally, we examined PDE6C-L858V, which models PDE6B-L854V, an RP-linked mutation that alters the protein isoprenyl modification. This analysis suggests that the type of prenyl modifications does not impact the folding of PDE6, but it modulates the enzyme affinity for its trafficking partner PDE6D. Hence, the pathogenicity of PDE6B-L854V likely arises from its trafficking deficiency. Taken together, our results demonstrate the effectiveness of the PDE6C expression system to evaluate pathogenicity and elucidate the mechanisms of PDE6 mutations in retinal diseases.

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Identification of Amino Acid Residues Responsible for the Selectivity of Tadalafil Binding to Two Closely Related Phosphodiesterases, PDE5 and PDE6

Cited by 34 publications

References 37 publications

Curcumin analogues inhibit phosphodiesterase-5 and dilate rat pulmonary arteries

Curcumin analogues inhibit phosphodiesterase-5 and dilate rat pulmonary arteries

Plasma Concentrations of Tadalafil in Children With Pulmonary Arterial Hypertension

Mechanisms of mutant PDE6 proteins underlying retinal diseases

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