The Oral Efficacy of Vardenafil Hydrochloride for Inducing Penile Erection in a Conscious Rabbit Model

Bischoff, Erwin; Niewoehner, U.; Haning, Helmut; Sayed, M.E.S.; Schenke, Thomas; Schlemmer, Karl‐Heinz

doi:10.1016/s0022-5347(01)69891-4

Cited by 44 publications

(9 citation statements)

References 11 publications

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“…It has been characterized as the major cGMP-hydrolyzing PDE in numerous tissues such as lung, platelets, pulmonary artery smooth muscle cells, and the penile corpus cavernosum (2,3). The abundance of PDE5 in smooth muscles and its role in regulating their contractile tone has made PDE5 an important drug target for the treatment of erectile dysfunction and pulmonary hypertension (2), leading to the development of potent PDE5 inhibitors, such as tadalafil (Cialis TM ) (4), vardenafil (Levitra TM ) (5), and sildenafil (Viagra TM and Revatio TM ) (6). All mammalian PDE families are dimeric and contain a homologous, but distinct C-terminal catalytic domain, whereas they differ more in their family-specific N-terminal regulatory domains.…”

mentioning

confidence: 99%

Solution Structure of the cGMP Binding GAF Domain from Phosphodiesterase 5

Heikaus

Stout

Sekharan

et al. 2008

Journal of Biological Chemistry

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Phosphodiesterase 5 (PDE5) controls intracellular levels of cGMP through its regulation of cGMP hydrolysis. Hydrolytic activity of the C-terminal catalytic domain is increased by cGMP binding to the N-terminal GAF A domain. We present the NMR solution structure of the cGMP-bound PDE5A GAF A domain. The cGMP orientation in the buried binding pocket was defined through 37 intermolecular nuclear Overhauser effects. Comparison with GAF domains from PDE2A and adenylyl cyclase cyaB2 reveals a conserved overall domain fold of a six-stranded ␤-sheet and four ␣-helices that form a well defined cGMP binding pocket. However, the nucleotide coordination is distinct with a series of altered binding contacts. The structure suggests that nucleotide binding specificity is provided by Asp-196, which is positioned to form two hydrogen bonds to the guanine ring of cGMP. An alanine mutation of Asp-196 disrupts cGMP binding and increases cAMP affinity in constructs containing only GAF A causing an altered cAMP-bound structural conformation. NMR studies on the tandem GAF domains reveal a flexible GAF A domain in the absence of cGMP, and indicate a large conformational change upon ligand binding. Furthermore, we identify a region of ϳ20 residues directly N-terminal of GAF A as critical for tight dimerization of the tandem GAF domains. The features of the PDE5 regulatory domain revealed here provide an initial structural basis for future investigations of the regulatory mechanism of PDE5 and the design of GAF-specific regulators of PDE5 function.Intracellular concentrations of the second messengers cAMP and cGMP are tightly regulated by the rate of synthesis through cyclases and hydrolysis through cyclic nucleotide phosphodiesterases (PDEs) 3 (1). The cGMP-specific, cGMP-binding phosphodiesterase, PDE5, is one of eleven identified PDE families. It has been characterized as the major cGMP-hydrolyzing PDE in numerous tissues such as lung, platelets, pulmonary artery smooth muscle cells, and the penile corpus cavernosum (2, 3). The abundance of PDE5 in smooth muscles and its role in regulating their contractile tone has made PDE5 an important drug target for the treatment of erectile dysfunction and pulmonary hypertension (2), leading to the development of potent PDE5 inhibitors, such as tadalafil (Cialis TM

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mentioning

confidence: 99%

Solution Structure of the cGMP Binding GAF Domain from Phosphodiesterase 5

Heikaus

Stout

Sekharan

et al. 2008

Journal of Biological Chemistry

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“…The sulfonic acid 1 was reacted with thionyl chloride yielding the sulfochloride 1a as intermediate which was directly converted with N-acetylpiperazine 2 to give the starting material 3 for the radiosynthesis. The acetyl moiety was reduced with freshly prepared lithium aluminum tritide [1] to the ethyl functionality.…”

Section: Resultsmentioning

confidence: 99%

“…Receptor binding studies of vardenafil, 1 Levitra 1 , a phosphodiesterase type V inhibitor against erectile dysfunction, required the synthesis of the tritium labeled compound 4. The complete synthesis is depicted in Scheme 1.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of [³H] vardenafil, Levitra^®, using a new labeling technique

Pleiß

2003

Labelled Comp Radiopharmac

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SummaryTritium was introduced into the new orally active, selective phosphodiesterase type V (PDE V) inhibitor vardenafil (Levitra 1 ), by reduction of a suitable amide precursor with freshly prepared lithium aluminum tritide. A specific activity of 52.7 Ci/mmol (1.95 TBq/mmol) was achieved. In order to overcome the usual technical difficulties during the preparation of complex tritides a new and easy labeling technique which has considerable potential for various tritiation procedures, was developed.

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“…Erectile responses occurred more quickly, were of larger magnitude, and were sustained for longer durations for vardenafil than for sildenafil. In a conscious rabbit model (Figure 4), intravenously administered vardenafil dose‐dependently facilitated erectile responses with or without simultaneous administration of SNP [24–27]. The minimal effective dose that significantly facilitated erection was 0.1 mg/kg for vardenafil vs. 1 mg/kg for sildenafil.…”

Section: Physiological Studies In Animal Modelsmentioning

confidence: 99%