Phosphodiesterase: Overview of protein structures, potential therapeutic applications and recent progress in drug development

Cellular and Molecular Life Sciences

Volumn 62, Issue 11, 2005, Pages 1198-1220

  Jeon, Y H ^a   Heo, Y S ^a   Kim, C M ^a   Hyun, Y L ^a   Lee, T G ^a   Ro, S ^a   Cho, J M ^a  

^a CrystalGenomics Inc   (South Korea)

Author keywords

3D structure; cAMP; cGMP; Drug discovery; Phosphodiesterase

Indexed keywords

1 [6 CHLORO 4 (3,4 METHYLENEDIOXYBENZYLAMINO) 2 QUINAZOLINYL] 4 PIPERIDINECARBOXYLIC ACID; 1 BUTYL 3 PROPYLXANTHINE; 4 [2 [3 (CYCLOPENTYLOXY) 4 METHOXYPHENYL] 2 PHENYLETHYL]PYRIDINE; AMRINONE; ANAGRELIDE; AROFYLLINE; AVANAFIL; CILOMILAST; CILOSTAZOL; DOXOFYLLINE; E 4010; E 8010; ENOXIMONE; MILRINONE; PHOSPHODIESTERASE; PHOSPHODIESTERASE I; PHOSPHODIESTERASE III; PHOSPHODIESTERASE III INHIBITOR; PHOSPHODIESTERASE INHIBITOR; PHOSPHODIESTERASE IV; PHOSPHODIESTERASE IV INHIBITOR; PHOSPHODIESTERASE IX; PHOSPHODIESTERASE V; PHOSPHODIESTERASE V INHIBITOR; PICLAMILAST; PIMOBENDAN; PIPERANOMETOZINE; ROFLUMILAST; ROLIPRAM; SCH 51866; SILDENAFIL; TADALAFIL; THEOPHYLLINE; UDENAFIL; UK 357903; UNCLASSIFIED DRUG; VARDENAFIL; VERAPAMIL; VINPOCETINE; ZAPRINAST;

AMINO ACID SEQUENCE; AMINO TERMINAL SEQUENCE; ASTHMA; BRONCHODILATATION; CANCER; CARBOXY TERMINAL SEQUENCE; CARDIOTOXICITY; CHRONIC OBSTRUCTIVE LUNG DISEASE; CLINICAL TRIAL; COMPLEX FORMATION; CONGESTIVE CARDIOMYOPATHY; CRYSTAL STRUCTURE; DEGENERATIVE DISEASE; DEMENTIA; DEPRESSION; DIARRHEA; DRUG ABSORPTION; DRUG ACTIVITY; DRUG BINDING; DRUG DESIGN; DRUG HALF LIFE; DRUG MECHANISM; DRUG SYNTHESIS; ENZYME ACTIVE SITE; ENZYME INHIBITION; ENZYME PHOSPHORYLATION; ERECTILE DYSFUNCTION; FORCED EXPIRATORY VOLUME; GENOMICS; HEADACHE; HEART FAILURE; HEART INFARCTION; HUMAN; LUNG DISEASE; NAUSEA; NEUROTOXICITY; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; OSTEOPOROSIS; PROTEIN DOMAIN; PROTEIN STRUCTURE; PROTEIN TARGETING; PROTEOMICS; PULMONARY HYPERTENSION; REVIEW; RHEUMATOID ARTHRITIS; SCHIZOPHRENIA; SEQUENCE ANALYSIS; SEXUAL DYSFUNCTION; SIDE EFFECT; STROKE; THROMBOCYTOPENIA; THROMBOCYTOSIS; VASCULAR DISEASE; VOMITING; X RAY DIFFRACTION;

DISEASE; DRUG DESIGN; DRUG THERAPY; HUMANS; MODELS, MOLECULAR; PHOSPHODIESTERASE INHIBITORS; PHOSPHORIC DIESTER HYDROLASES; PROTEIN STRUCTURE, TERTIARY; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 21144437565     PISSN: 1420682X     EISSN: None     Source Type: Journal    
DOI: 10.1007/s00018-005-4533-5     Document Type: Review

References (254)

1. Beavo J. A. (1995) Cyclic nucleotide phosphodiesterases: functional implications of multiple isoforms. Physiol. Rev. 75: 725-748
2. Soderling S. H. and Beavo J. A. (2000) Regulation of cAMP and cGMP signaling: new phosphodiesterases and new functions. Curr. Opin. Cell Biol. 12: 174-179
3. Corbin J. D. and Francis, S. H. (1999) Cyclic GMP phosphodiesterase-5: target of sildenafil. J. Biol. Chem. 274: 13729-13732
4. Beavo J. A., M. Conti and R. J. Heaslip. (1994) Multiple cyclic nucleotide phosphodiesterases. Mol. Pharmacol. 46: 399-3405
5. Bolger G. B. (1994) Molecular biology of the cyclic AMP-specific cyclic nucleotide phosphodiesterases: a diverse family of regulatory enzymes. Cell. Signal. 6: 851-859.
6. Mehats C., Andersen C. B., Filopanti M., Jin S. L. and Conti M. (2002) Cyclic nucleotide phosphodiesterases and their role in endocrine cell signaling. Trends Endocr. Met. 13: 29-35
7. Perry M. J. and Higgs G. A. (1998) Chemotherapeutic potential of phosphodiesterase inhibitors. Curr. Opin. in Chem. Biol. 2: 472-481
8. Rotella D. P. (2002) Phosphodiestease 5 inhibitors: current status and potential applications. Nat. Rev. Drug Discov. 1: 674-682
9. Conti M., Nemoz G., Sette C. and Vicini E. (1995) Recent progress in understanding the hormonal regulation of phosphodiesterases. Endocr. Rev. 16: 370-389
10. Torphy T. J. (1998) Phosphodiesterase isozymes. Am. J. Respir. Crit. Care Med. 157: 351-370
11. Krebs E. G. and J. A. Beavo. (1979) Phosphorylation-dephosphorylation of enzymes. Annu. Rev. Biochem. 48: 923-959
12. Levin R. M. and Weiss B. (1976) Mechanism by which psychotropic drugs inhibit adenosine cyclic 39,59-monophosphate phosphodiesterase of brain. Mol. Pharmacol. 12: 581-589
13. Hidaka H., T. Tanaka and Itoh H. (1984) Selective inhibitors of three forms of cyclic nucleotide phosphodiesterases. Trends Pharmacol. Sci. 5: 237-239
14. Wells J. N., Garst J. E. and Kramer G. L. (1981) Inhibition of separated forms of cyclic nucleotide phosphodiesterase from pig coronary arteries by 1,3-disubstituted and 1,3,8-trisubstituted xanthines. J. Med. Chem. 24: 954-958
15. Wood M. A. and Hess M. L. (1989) Review: long-term oral therapy of congestive heart failure with phosphodiesterase inhibitors. Am. J. Med. Sci. 297: 105-113
16. Information obtained from the Investigational Drugs Database (IDDB, www.iddb3.com)
17. Xu R. X., Hassell A. M., Vanderwall D., Lambert M. H., Holmes W. D., Luther M. A. et al. (2000) Atomic structure of PDE 4: insights into phosphodiesterase mechanism and specificity. Science 288: 1822-1825
18. Xu R. X., Rocque W. J., Lambert M. H., Vanderwall D. E., Luther M. A. and Nolte R. T. (2004) Crystal structures of the catalytic domain of phosphodiesterase 4B complexed with AMP, 8-Br-AMP and rolipram. J. Mol. Biol. 337: 355-365
19. Lee M. E., Markowitz J., Lee J. O. and Lee, H. (2002) Crystal structure of phosphodiesterase 4D and inhibitor complex. FEBS Lett. 530: 53-58
20. Huai Q., Wang H., Sun Y., Kim H. Y., Liu Y. and Ke H. (2003) Three-dimensional structures of PDE4D in complex with roliprams and implication on inhibitor selectivity. Structure 11: 865-873
21. Huai Q., Colicelli J. and Ke H. (2003) The crystal structure of AMP-bound PDE4 suggests a mechanism for phosphodiesterase catalysis. Biochemistry 42: 13220-13226
22. Huai Q., Liu Y., Francis S. H., Corbin J. D. and Ke H. (2004) Crystal structures of phosphodiesterases 4 and 5 in complex with inhibitor 3-isobutyl-1-methylxanthine suggest a conformation determinant of inhibitor selectivity. J. Biol. Chem. 279: 13095-13101
23. Sung B. J., Hwang K. Y., Jeon Y. H., Lee J. I., Heo Y. S., Kim J. H. et al. (2003) Structure of the catalytic domain of human phosphodiesterase 5 with bound drug molecules. Nature 425: 98-102
24. Scapin G., Patel S. B., Chung C., Varnerin J. P., Edmondson S. D., Mastracchio A. et al. (2004) Crystal structure of human phosphodiesterase 3B: atomic basis for substrate and inhibitor specificity. Biochemistry 43: 6091-6100
25. Zhang K. Y., Card G. L., Suzuki Y., Artis D. R., Fong D., Gillette S. et al. (2004) A glutamine switch mechanism for nucleotide selectivity by phosphodiesterases. Mol. Cell. 15: 279-286
26. Huai Q., Wang H., Zhang W., Colman R. W., Robinson H. and Ke H. (2004) Crystal structure of phosphodiesterase 9 shows orientation variation of inhibitor 3-isobutyl-1-methylxanthine binding. Proc. Natl. Acad. Sci. USA 101: 9624-9629
27. Beavo J. A. and Brunton L. L. (2002) Cyclic nucleotide research-still expanding after half a century. Nat. Rev. Mol. Cell Biol. 3: 710-716
28. Conti M. (2000) Phosphodiesterases and cyclic nucleotide signaling in endocrine cells. Mol. Endocrinol. 14: 1317-1327
29. Mehats C., Andersen C. B., Filopanti M., Jin S. L. and Conti M. (2002) Cyclic nucleotide phosphodiesterases and their role in endocrine cell signaling. Trends Endocrinol. Metab. 13: 29-35
30. Thompson W. J. (1991) Cyclic nucleotide phosphodiesterases: pharmacology, biochemistry and function. Pharmacol. Ther. 51: 13-33
31. Bolger G. B. (1994) Molecular biology of the cyclic AMP-specific cyclic nucleotide phosphodiesterases: a diverse family of regulatory enzymes. Cell. Signal. 6: 851-859
32. Houslay M. D. and Adams D. R. (2003) PDE4 cAMP phosphodiesterases: modular enzymes that orchestrate signalling cross-talk, desensitization and compartmentalization. Biochem. J. 370: 1-18
33. Sonnenburg W. K., Seger D., Kwak K. S., Huang J., Charbonneau H. and Beavo J. A. (1995) Identification of inhibitory and calmodulin-binding domains of the PDE1A1 and PDE1A2 calmodulin-stimulated cyclic nucleotide phosphodiesterases. J. Biol. Chem. 270: 30989-31000
34. See [17]
35. See [18]
36. See [19]
37. See [20]
38. See [21]
39. See [22]
40. See [25]
41. See [24]
42. See [25]
43. See [26]
44. Percival M. D., Yeh B. and Falgueyret J. P. (1997) Zinc dependent activation of cAMP-specific phosphodiesterase (PDE4A). Biochem. Biophys. Res. Commun. 241: 175-180
45. Laliberte F., Han Y., Govindarajan A., Giroux A., Liu S., Bobechko B. et al. (2000) Conformational difference between PDE4 apoenzyme and holoenzyme. Biochemistry 39: 6449-6458
46. Kovala T., Sanwal B. D. and Ball E. H. (1997) Recombinant expression of a type IV, cAMP-specific phosphodiesterase: characterization and structure-function studies of deletion mutants. Biochemistry 36: 2968-2976
47. Francis S. H., Colbran J. L., McAllister-Lucas L. M. and Corbin J. D. (1994) Zinc interactions and conserved motifs of the cGMP-binding cGMP-specific phosphodiesterase suggest that it is a zinc hydrolase. J. Biol. Chem. 269: 22477-22480
48. Howell R. E., Sickels B. D. and Woeppel S. L. (1993) Pulmonary antiallergic and bronchodilator effects of isozyme-selective phosphodiesterase inhibitors in guinea pigs. J. Pharmacol. Exp. Ther. 264: 609-615
49. Raeburn D., Underwood S. L., Lewis S. A., Woodman V. R., Battram C. H., Tomkinson A. et al. (1994) Anti-inflammatory and bronchodilator properties of RP 73401, a novel and selective phosphodiesterase type IV inhibitor. Br. J. Pharmacol. 113: 1423-1431
50. Hughes B., Howat D., Lisle H., Holbrook M., James T., Gozzard N. et al. (1996) The inhibition of antigen-induced eosinophilia and bronchoconstriction by CDP840, a novel stereo-selective inhibitor of phosphodiesterase type 4. Br. J. Pharmacol. 118: 1183-1191
51. Gozzard N., el Hashim A., Herd C. M., Blake S. M., Holbrook M., Hughes B. et al. (1996) Effect of the glucocorticosteroid budesonide and a novel phosphodiesterase type 4 inhibitor CDP840 on antigen-induced airway responses in neonatally immunized rabbits. Br. J. Pharmacol. 118: 1201-1208
52. Turner C. R., Andersen C. J., Smith W. B. and Watson J. W. (1994) Effects of rolipram on responses to acute and chronic antigen exposure in monkeys. Am. J. Respir. Crit. Care Med. 149: 1153-1159
53. Elwood W, Sun J., Barnes P. J., Giembycz M. A. and Chung K. F. (1995) Inhibition of allergen-induced lung eosinophilia by type-III and combined type III- and IV-selective phosphodiesterase inhibitors in brown-Norway rats. Inflamm. Res. 44: 83-86
54. Piaz V. D. and Giovannoni M. P. (2000) Phosphodiesterase 4 inhibitors, structurally unrelated to rolipram, as promising agents for the treatment of asthma and other pathologies. Eur. J. Med. Chem. 35: 463-480
55. Schudt C., Tenor H. and Hatzelmann A. (1995) PDE isoenzymes as targets for anti-asthma drugs. Eur. Respir. J. 8: 1179-1183
56. Schudt C., Gantner F., Tenor H. and Hatzelmann A. (1999) Therapeutic potential of selective PDE inhibitors in asthma. Pulm. Pharmacol. Ther. 12:123-129
57. MacIntyre N. R. (2004) Chronic obstructive pulmonary disease: emerging medical therapies. Respiratory Care. 49: 64-71
58. MacLean M. R., Johnston E. D., McCulloch K. M., Pooley L., Houslay M. and Sweeney G. (1997) Phosphodiesterase isoforms in the pulmonary arterial circulation of the rat: changes in pulmonary hypertension. J. Pharmacol. Exp. Ther. 283: 619-624
59. MacLean M. R., Sweeney G., Baird M., McCulloch K. M., Houslay M. and Morecroft I. (1996) 5-Hydroxytryptamine receptors mediating vasoconstriction in pulmonary arteries from control and pulmonary hypertensive rats. Br. J. Pharmacol. 119: 917-930
60. Schermuly R. T., Ghofrani H. A., Enke B., Weissmann N., Grimminger F., Seeger W. et al. (1999) Low-dose systemic phosphodiesterase inhibitors amplify the pulmonary vasodilatory response to inhaled prostacyclin in experimental pulmonary hypertension. Am. J. Respir. Crit Care. Med. 160: 1500-1506
61. Schermuly R. T., Roehl A., Weissmann N., Ghofrani H. A., Schudt C., Tenor H. et al. (2000) Subthreshold doses of specific phosphodiesterase type 3 and 4 inhibitors enhance the pulmonary vasodilatory response to nebulized prostacyclin with improvement in gas exchange. J. Pharmacol Exp. Ther. 292: 512-520
62. Schermuly R. T., Krupnik E., Tenor H., Schudt C., Weissmann N., Rose F. et al. (2001) Coaerosolization of phosphodiesterase inhibitors markedly enhances the pulmonary vasodilatory response to inhaled iloprost in experimental pulmonary hypertension: maintenance of lung selectivity. Am. J. Respir. Crit Care. Med. 164: 1694-1700
63. Schermuly R. T., Roehl A., Weissmann N., Ghofrani H.A., Leuchte H., Grimminger F. et al. (2001) Combination of nonspecific PDE inhibitors with inhaled prostacyclin in experimental pulmonary hypertension. Am. J. Physiol. Lung Cell Mol. Physiol. 281: L1361-L1368
64. Hanasato N., Oka M., Muramatsu M., Nishino M., Adachi H. and Fukuchi Y. (1999) E-4010, a selective phosphodiesterase 5 inhibitor, attenuates hypoxic pulmonary hypertension in rats. Am. J. Physiol. 277: L225-L232
65. Yamamoto T., Wada A., Tsutamoto T., Ohnishi M. and Horie M. (2004) Long-term treatment with a phosphodiesterase type 5 inhibitor improves pulmonary hypertension secondary to heart failure through enhancing the natriuretic peptides-cGMP pathway. J. Cardiovasc. Pharmacol. 44: 596-600
66. Pauvert O., Bonnet S., Rousseau E., Marthan R. and Savineau J. P. (2004) Sildenafil alters calcium signaling and vascular tone in pulmonary arteries from chronically hypoxic rats. Am. J. Physiol. Lung Cell Mol. Physiol. 287: 577-583
67. Sebkhi A., Strange J. W., Phillips S. C., Wharton J. and Wilkins M. R. (2003) Phosphodiesterase type 5 as a target for the treatment of hypoxia-induced pulmonary hypertension. Circulation 107: 3230-3235
68. Sausbier M., Schubert R., Voigt V., Hirneiss C., Pfeifer A., Korth M. et al. (2000) Mechanisms of NO/cGMP-dependent vasorelaxation. Circ. Res. 87: 825-830
69. Ballard S. A., Gingell C. J., Tang K., Turner L. A., Price M. E. and Naylor A. M. (1998) Effects of sildenafil on the relaxation of human corpus cavernosum tissue in vitro and on the activities of cyclic nucleotide phosphodiesterase isozymes. J. Urol. 159: 2164-2171
70. Lue T. F. (2000) Erectile dysfunction. N. Engl. J. Med. 324: 1802-1813
71. O'Connell H. E., Hutson J. M., Anderson C. R. and Plenter R. J. (1998) Anatomical relationship between urethra and clitoris. J. Urol. 159: 1892-1897
72. Burnett A. L., Calvin D. C., Silver R. I., Peppas D. S. and Docimo S. G. (1997) Immunohistochemical description of nitric oxide synthase isoforms in human clitoris. J. Urol. 158: 75-78
73. Park K., Moreland R. B., Goldstein I. Atala A. and Traish A. (1998) Sildenafil inhibits phosphodiesterase type 5 in human clitoral corpus cavernosum smooth muscle. Biochem. Biophys. Res. Commun. 249: 612-617
74. Caruso S., Intelisano G., Lupo L. and Agnello C. (2001) Premenopausal women affected by sexual arousal disorder treated with sildenafil: a double-blind, cross-over, placebo-controlled study. Br. J. Obstet. Gynecol. 108: 623-628
75. Segraves R. T. (2003) Emerging therapies for female sexual dysfunction. Expert. Opin. Emerg. Drugs 8: 515-522
76. Beavo J. A. (1995) Cyclic nucleotide phosphodiesterases: functional implications of multiple isoforms. Physiol. Rev. 75: 725-743
77. Kincaid R. L., Balaban C. D. and Billingsley M. L. (1992) Regional and developmental expression of calmodulin dependent cyclic nucleotide phosphodiesterase in rat brain. Adv. Sec. Mess. Phosphoprot. Res. 25: 111-122
78. Mcafee D. A., Schorderet M. and Greengard P. (1971) Adenosine 3′,5′-monophosphate in nervous tissue: increase associated with synaptic transmission. Science 171: 1156-1158
79. Rydel R. E. and Greene L. A. (1988) cAMP analogs promote survival and neurite outgrowth in cultures of rat sympathetic and sensory neurons independently of nerve growth factor. Proc. Natl. Acad. Sci. USA 85: 1257-1261
80. Brenneman D. E., Fitzgerald S. and Litzinger M. J. (1985) Neuronal survival during electrical blockade is increased by 8-bromocyclic adenosine 3′,5′-monophosphate. J. Pharmacol. Exp. Ther. 233: 402-408
81. Hartikka J., Staufenbiel M. and Lubbert H. (1992) Cyclic AMP, but not basic FGF, increases the in vitro survival of mesencephalic dopaminergic neurons and protects them from MPP(+)-induced degeneration. J. Neurosci. Res. 32: 190-201
82. Nathanson J. A. (1977) Cyclic nucleotides and nervous system function. Physiol. Rev. 57: 157-256
83. Nishino N., Kitamura N., Hashimoto T. and Tanaka C. (1993) Transmembrane signalling systems in the brain of patients with Parkinson's disease. Rev. Neurosci. 4: 213-222
84. Kakkar R., Raju R. V. S., Rajput A. and Sharma R. K. (1996) Inhibition of bovine brain calmodulin-dependent cyclic nucleotide phosphodiesterase isozymes by deprenyl. Life Sci. 59: 337-341
85. Kakkar R., Raju R. V. S., Rajput A. and Sharma R. K. (1997) Amantadine: an antiparkinsonian agent inhibits bovine brain 60 kDa calmodulin-dependent cyclic nucleotide phosphodiesterase isozyme. Brain. Res. 749: 290-294
86. Sorimachi H., Ishiura S. and Suzuki K. (1997) Structure and physiological function of calpains. Biochem. J. 328: 721-732
87. Li J., Nixon R., Messer A., Berman S. and Bursztajn S. (1998) Altered gene expression for calpain:calpastatin system in motor neuron degeneration (Mnd) mutant mouse brain and spinal cord. Brain. Res. Mol. Brain Res. 53: 174-186
88. Saido T. C., Sorimachi S. and Suzuki K. (1994) Calpain: new perspectives in molecular diversity and physiological and pathological involvement. FASEB J. 8: 814-822
89. Croall D. E. and Demartino G. N. (1991) Calcium activated neutral protease (calpain) system: structure, function and regulation. Physiol. Rev. 71: 813-847
90. Saito K. I., Elce J. S., Hamos J. E. and Nixon R. A. (1993) Widespread activation of calcium activated neutral proteinase (calpain) in the brain in Alzeimer's disease: a potential molecular basis for neuronal degeneration. Proc. Natl. Acad. Sci. USA 90: 2628-2632
91. Kakkar R., Raju R. V. S. and Shanna R. K. (1998) In vitro generation of an active calmodulin-independent phosphodiesterase from brain calmodulin-dependent phosphodiesterase (PDE1A2) by m-calpain. Arch. Biochem. Biophys. 358: 320-328
92. Tully T. (1997) Regulation of gene expression and its role in longterm memory and synaptic plasticity. Proc. Natl. Acad. Sci. USA 94: 4239-4241
93. Yin J. C., Wallach J. S., Del Vecchio M., Wilder E. L., Zhou H., Quinn W. G. et al. (1994) Induction of a dominant negative CREB transgene specifically blocks long-term memory in Drosophila. Cell 79: 49-58
94. Bourtchuladze R., Frenguelli B., Blendy J., Cioffi D., Schutz G. and Silva A. J. (1994) Deficient long-term memory in mice with a targeted mutation of the cAMP-responsive element-binding protein. Cell 79: 59-68
95. Lamprecht R., Hazvi S. and Dudai Y. (1997) cAMP response element-binding protein in the amygdala is required for long but not short-term conditioned taste aversion memory. J. Neurosci. 17: 8443-8450
96. Guzowski J. and McGaugh J. (1997) Antisense oligodeoxynucleotide-mediated disruption of hippocampal cAMP response element binding protein levels impairs consolidation of memory for water maze training. Proc. Natl. Acad. Sci. USA 94: 2693-2698
97. Pittenger C., Huang Y. Y., Paletzki R. F., Bourtchouladze R., Scanlin H., Vronskaya S. et al. (2002) Reversible inhibition of CREB/ATF transcription factors in region CA1 of the dorsal hippocampus disrupts hippocampus-dependent spatial memory. Neuron 34: 447-462
98. Kida S., Josselyn S. A., de Ortiz S. P., Kogan J. H., Chevere I., Masushige S. et al. (2002) CREB required for the stability of new and reactivated fear memories. Nat. Neurosci. 5: 348-355
99. Yin J., Del Vecchio M., Zhou H. and Tully T. (1995) CREB as a memory modulator: induced expression of dCREB2 activator isoform enhances long-term memory in Drosophila. Cell 81: 107-115
100. Josselyn S. A., Shi C., Carlezon W. A. Jr, Neve R. E., Nestler E. J. and Davis M. (2001) Long term memory is facilitated by cAMP response element-binding protein overexpression in the amygdala. J. Neurosci. 21: 2404-2412
101. Bartsch D., Ghirardi M., Skehel P. A., Karl K. A., Herder S. P., Chen M. et al. (1995) Aplysia CREB2 represses long-term facilitation: relief of repression converts transient facilitation into long-term functional and structural change. Cell 83: 979-992
102. Martin K. C., Casadio A., Zhu H., Yaping E., Rose J. C., Chen M. et al. (1997) Synapse-specific, long-term facilitation of Aplysia sensory to motor synapses: a function for local protein synthesis in memory storage. Cell 91: 927-938
103. Casadio A., Martin K. C., Giustetto M., Zhu H., Chen M., Bartsch D. et al. (1999) A transient, neuron-wide form of CREB mediated long-term facilitation can be stabilized at specific synapses by local protein synthesis. Cell 99: 221-237
104. Dash P., Hochner B. and Kandel E. (1990) Injection of the cAMP responsive element into the nucleus of Aplysia sensory neurons blocks long-term facilitation. Nature 345: 718-721
105. Barco A., Alarcon J. M. and Kandel E. R. (2002) Expression of constitutively active CREB protein facilitates the late phase of long-term potentiation by enhancing synaptic capture. Cell 108: 689-703
106. Davis G. W., Schuster C. M. and Goodman C. S. (1996) Genetic dissection of structural and functional components of synaptic plasticity. III. CREB is necessary for presynaptic functional plasticity. Neuron 17: 669-679
107. Sanyal S., Sandstrom D. J., Hoeffer C. A. and Ramaswami M. (2002) AP-1 functions upstream of CREB to control synaptic plasticity in Drosophila. Nature 416: 870-874
108. Tully T., Bourtchouladze R., Scott R. and Tallman J. (2003) Targeting the CREB pathway for memory enhancers. Nat. Rev. in Drug Discov. 2: 267-277
109. Boess F. G., Hendrix M., van der Staay F. J., Erb C., Schreiber R., van Staveren W. et al. (2004) Inhibition of phosphodiesterase 2 increases neuronal cGMP, synaptic plasticity and memory performance. Neuropharmacology 47: 1081-1092
110. Pérez-Torres S., Cortés R., Tolnay M., Probst A., Palacios J.M., and Mengoda G. (2003) Alterations on phosphodiesterase type 7 and 8 isozyme mRNA expression in Alzheimer's disease brains examined by in situ hybridization. Exp. Neurol. 182: 322-334
111. Koyama H., Bomfeldt K. E., Fukumoto S. and Nishizawa Y. (2001). Molecular pathways of cyclic nucleotide-induced inhibition of arterial smooth muscle cell proliferation. J. Cell Physiol. 186: 1-10
112. Kondo K., Umemura K., Miyaji M. and Nakashima, M. (1999) Milrinone, a phosphodiesterase inhibitor, suppresses intimal thickening after photochemically induced endothelial injury in the mouse femoral artery. Atherosclerosis 142: 133-138
113. Rybalkin S. D., Rybalkina I., Beavo J. A. and Bornfeldt K. E. (2002) Cyclic nucleotide phosphodiesterase 1C promotes human arterial smooth muscle cell proliferation. Circ. Res. 90: 151-157
114. Stern M. P. (1995) Diabetes and cardiovascular disease: the 'common soil' hypothesis. Diabetes 44: 369-374
115. Taegtmeyer H. (1996) Insulin resistance and atherosclerosis: common roots for two common diseases? Circulation 93: 1777-1779
116. Sowers J. R. (1997) Insulin and insulin-like growth factor in normal and phathological cardiovascular physiology. Hypertension 29: 691-699
117. Nagaoka T., Shirakawa T., Balon T. W., Russell J. C. and Fujita-Yamaguchi Y. (1998) Cyclic nucleotide phosphodiesterase 3 expression in vivo: evidence for tissue-specific expression of phosphodiesterase 3A or 3B mRNA and activity in the aorta and adipose tissue of atherosclerosis-prone insulin-resistant rats. Diabetes 47: 1135-1144
118. Netherton S. J., Jimmo S. L., Palmer D., Tilley D. G., Dunkerley H. A., Raymond D. R. et al. (2002) Altered phosphodiesterase 3-mediated cAMP hydrolysis contributes to a hypermotile phenotype in obese JCR: LA-cp rat aortic vascular smooth muscle cells: implications for diabetes-associated cardiovascular disease. Diabetes 51: 1194-1200
119. Desouza C., Parulkar A., Lumpkin D., Akers D. and Fonseca V. A. (2002) Acute and prolonged effects of sildenafil on brachial artery flow-mediated dilation in type 2 diabetes. Diabetes Care 25: 1336-1339
120. Zhang R., Wang Y., Zhang L., Zhang Z., Tsang W., Lu M. et al. (2002) Sildenafil (Viagra) induces neurogenesis and promotes functional recovery after stroke in rats. Stroke 33: 2675-2680
121. Kahn S. E. (2003) The relative contribution of insulin resistance and beta cell dysfunction to the pathophysiology of Type 2 diabetes. Diabetologia 46: 3-19
122. Juhl C. B., Hollingdal M., Sturis J., Jakobsen G., Agerso H., Veldhuis J. et al. (2002) Bedtime administration of NN221, a long-acting GLP-1 derivative, substantially reduces fasting and postprandial glucose in type 2 diabetes. Diabetes 51: 424-429
123. Rachman J., Barrow B. A., Levy J. C. and Turner R. C. (1997) Near-normalisation of diurnal glucose concentrations by continuous administration of glucagon-like peptide-1 (GLP-1) in subjects with NIDDM. Diabetologia 40: 205-211
124. Reinhardt R. R., Chin E., Zhou J., Taira M., Murata T., Manganiello V. C. et al. (1995) Distinctive anatomical patterns of gene expression for cGMP-inhibited cyclic nucleotide phosphodiesterases. J. Clin. Invest. 95: 1528-1538
125. Beavo J. A. (1995) Cyclic nucleotide phosphodiesterases: functional implications of multiple isoforms. Physiol. Rev. 75: 725-748
126. Shakur Y., Holst L. S., Landstrom T. R., Movsesian M, Degerman E and Manganiello V. (2001) Regulation and function of the cyclic nucleotide phosphodiesterase (PDE3) gene family. Prog. Nucleic Acid Res. Mol. Biol. 66: 241-277
127. Manganiello V. C., Taira M., Degerman E. and Belfrage P. (1995) Type III cGMP-inhibited cyclic nucleotide phosphodiesterases (PDE3 gene family). Cell. Signal. 7: 445-455
128. Beebe S. J., Redmon J. B., Blackmore P. F. and Corbin J. D. (1985) Discriminative insulin antagonism of stimulatory effects of various cAMP analogs on adipocyte lipolysis and hepatocyte glycogenolysis. J. Biol. Chem. 260: 15781-15788
129. Rahn T., Ridderstrale M., Tornqvist H., Manganiello V. Fredrikson G., Belfrage P. et al. (1994) Essential role of phosphatidylinositol 3-kinase in insulin-induced activation and phosphorylation of the cGMP-inhibited cAMP phosphodiesterase in rat adipocytes. Studies using the selective inhibitor wortmannin. FEBS Lett. 350: 314-318
130. Liang L., Beshay E. and Prud'homme G. J. (1998) The phosphodiesterase inhibitors pentoxifylline and rolipram prevent diabetes in NOD mice. Diabetes. 47: 570-575
131. Lazner F., Gowen M., Pavasovic D. and Kola I. (1998) Osteopetrosis and osteoporosis: two sides of the same coin. Hum. Mol. Genet. 8(10): 1839-1846
132. Mahavni V. and Sood A. K. (2001) Hormone replacement therapy and cancer risk. Curr. Opin. Oncol. 13: 384
133. Miller P. D., Woodson G., Licata A. A., Ettinger M. P., Mako B., Smith M. E. et al. (2000) Rechallenge of patients who had discontinued alendronate therapy because of upper gastrointestinal symptoms. Clin. Ther. 22: 1433
134. Farndale R.W., Sandy J. R., Atkinson S. J., Pennington S. R., Meghji S. and Meikle M. C. (1988) Parathyroid hormone and prostaglandin E2 stimulate both inositol phosphates and cyclic AMP accumulation in mouse osteoblast cultures. Biochem. J. 252: 263-268
135. Kumegawa M., Ikeda E., Tanaka S., Haneji T., Yora T., Sakagishi Y. et al. (1984) The effects of prostaglandin E2, parathyroid hormone, 1,25 dihydroxycholecalciferol and cyclic nucleotide analogs on alkaline phosphatase activity in osteoblastic cells. Calcif. Tissue. Int. 36: 72-76
136. Ishizuya T., Yokose S., Hori M., Noda T., Suda T., Yoshiki S. et al. (1997) Parathyroid hormone exerts disparate effects on osteoblast differentiation depending on exposure time in rat osteoblastic cells. J. Clin. Invest. 99: 2961-2970
137. Partridge N. C., Bloch S. R. and Pearman A. T. (1994) Signal transduction pathways mediating parathyroid hormone regulation of osteoblastic gene expression. J. Cell. Biochem. 55: 321-327
138. Jee W. S., Ueno K., Deng Y. P. and Woodbury D. M. (1985) The effects of prostaglandin E2 in growing rats: increased metaphyseal hard tissue and cortico-endosteal bone formation. Calcif. Tissue. Int. 37: 148-157
139. Jee W. S., Ueno K., Kimmel D. B., Woodbury D. M., Price P. and Woodbury L. A. (1987) The role of bone cells in increasing metaphyseal hard tissue in rapidly growing rats treated with prostaglandin E2. Bone 8: 171-178
140. High W. B. (1987) Effects of orally administered prostaglandin E-2 on cortical bone turnover in adult dogs: a histomorphometric study. Bone 8: 363-373
141. Whitfield J. F. and Morley P. (1995) Small bone-building fragments of parathyroid hormone: new therapeutic agents for osteoporosis. Trends Pharmacol. Sci. 16: 382-386
142. Reeve J. (1996) PTH: A future role in the management of osteoporosis? J. Bone. Miner. Res. 11: 440-445
143. Finkelstein J. S., Klibanski A., Schaefer E. H., Hornstein M. D., Schiff I. and Neer R. M. (1994) Parathyroid hormone for the prevention of bone loss induced by estrogen deficiency. N. Engl. J. Med. 331: 1618-1623
144. Waki Y., Horita T., Miyamoto K., Ohya K. and Kasugai S. (1999) Effects of XT-44, a phosphodiesterase 4 inhibitor, in osteoblastgenesis and osteoclastgenesis in culture and its therapeutic effects in rat osteopenia models. Jpn. J. Pharmacol. 79: 477-483
145. Kasugai S. and Miyamoto K. (1999) Potential of PDE4 inhibitors in the treatment of osteopenia. Drug News Perspect. 12: 529-534
146. Kinoshita T., Kobayashi S., Ebara S., Yoshimura Y., Horiuchi H., Tsutsumimoto T. et al. (2000) Phosphodiesterase inhibitors, Pentoxifylline and Roliplam, increase bone mass mainly by promoting bone formation in normal mice. Bone 27:811-817
147. Dyke H. J. and Montana J. G. (2002) Update on the therapeutic potential of PDE4 inhibitors. Expert Opin. Investig. Drugs 11: 1-13.
148. Souness J. E. and Foster M. (1998) Potential of phosphodiesterase Type IV inhibitors in the treatment of reumatoid arthritis. IDrugs 1: 541-553
149. Hirsha L., Dantesa A., Suhb B. S., Yoshidac Y., Hosokawac K., Tajimac K. et al. (2004) Phosphodiesterase inhibitors as anti-cancer drugs. Bio. Pharm. 68: 981-988
150. Stork P. J. and Schmitt J. M. (2002) Crosstalk between cAMP and AP kinase signaling in the regulation of cell proliferation. Trends Cell. Biol. 12: 258-266
151. Yoshida Y, Hosokawa K., Dantes A., Tajima K., Kotsuji F. and Amsterdam A. (2000) Theophylline and cisplatin synergize in down regulation of BCL-2 induction of apoptosis in human granulosa cells transformed by a mutated p53 (p53 val135) and Ha-ras oncogene. Int. J. Oncol. 17: 227-235
152. Shmueli A. and Oren M. (2004) Regulation of p53 by Mdm2: fate is in the numbers. Mol. Cell. 13: 4-5
153. Hosokawa K., Aharoni D., Dantes A., Shaulian E., Schere-Levy C., Atzmon R. et al. (1998) Modulation of Mdm2 expression and p53-induced apoptosis in immortalized human ovarian granulosa cells. Endocrinology 139: 4688-4700
154. Glenn H. L. and Jacobson B. S. (2003) Cyclooxygenase and cAMP-dependent protein kinase reorganize the actin cytoskeleton for motility in HeLa cells. Cell. Motil. Cytoskeleton. 55: 265-77
155. Sasson R. and Amsterdam A. (2002) Stimulation of apoptosis in human granulose cells from in vitro fertilization patients and its prevention by dexamethasone: involvement of cell contact and bcl-2 expression. J. Clin. Endocrinol. Metab. 87: 3441-3451
156. Liu F., Verin A. D., Borbiev T. and Garcia J. G. (2001) Role of cAMP-dependent protein kinase A activity in endothelial cell cytoskeleton rearrangement. Am. J. Physiol. Lung. Cell. Mol. Physiol. 280(6): L1309-L1317
157. Youdim K. A., Qaiser M. Z., Begley D. J., Rice-Evans C. A. and Abbott N. J. (2004) Flavonoid permeability across an in situ model of the blood-brain barrier. Free. Radic. Biol. Med. 36: 592-604
158. Murata J., Ayukawa K., Ogasawara M., Watanabe H. and Saiki I. (1999) Induction of autocrine factor inhibiting cell motility from murine B16-BL6 melanoma cells by alpha-melanocyte stimulating hormone. Int. J. Cancer. 80: 889-895
159. Timoshenko A. V., Xu G., Chakrabarti S., Lala P. K. and Chakraborty C. (2003) Role of prostaglandin E2 receptors in migration of murine and human breast cancer cells. Exp. Cell. Res. 289: 265-274
160. Santibanez J. F., Olivares D., Guerrero J. and Martinez J. (2003) Cyclic AMP inhibits TGFbeta1-induced cell-scattering and invasiveness in murine-transformed keratinocytes. Int. J. Cancer. 107: 715-720
161. Yamanaka Y., Mammoto T., Kirita T., Mukai M., Mashimo T., Sugimura M. et al. (2002) Epinephrine inhibits invasion of oral squamous carcinoma cells by modulating intracellular cAMP. Cancer. Lett. 176: 143-148
162. Daniel V., Litwack G. and Tomkins G. M. (1973) Induction of cytolysis of cultured lymphoma cells by adenosine 3′:5′-cyclic monophosphate and the isolation of resistant variants. Proc. Natl. Acad. Sci. USA 70: 76-79
163. Lomo J., Blomhoff H. K., Beiske K., Stokke T. and Smeland E. B. (1995) TGF-beta 1 and cyclic AMP promote apoptosis in resting human B lymphocytes. J. Immunol. 154: 1634-1643
164. Knox K. A., Johnson G. D. and Gordon J. (1993) Distribution of cAMP in secondary follicles and its expression in B cell apoptosis and CD40-mediated survival. Int. Immunol. 5: 1085-1091
165. McConkey D. J., Orrenius S. and Jondal M. (1990) Agents that elevate cAMP stimulate DNA fragmentation in thymocytes. J. Immunol. 145: 1227-1230
166. Kizaki H., Suzuki K., Tadakuma T. and Ishimura Y. (1990) Adenosine receptor-mediated accumulation of cyclic AMP-induced T-lymphocyte death through internucleosomal DNA cleavage. J. Biol. Chem. 265: 5280-5284
167. Krett N. L., Zell J. L., Halgren R. G., Pillay S., Traynor A. E. and Rosen S.T. (1997) Cyclic adenosine-3′,5′-monophosphate-mediated cytotoxicity in steroid sensitive and resistant myeloma. Clin. Cancer. Res. 3: 1781-1787
168. Mentz E, Merle-Beral H. and Dalloul A. H. (1999) Theophyllineinduced B-CLL apoptosis is partly dependent on cyclic AMP production but independent of CD38 expression and endogenous IL-10 production. Leukemia 13: 78-84
169. Coffino P., Bourne H. R. and Tomkins G. M. (1975) Mechanism of lymphoma cell death induced by cyclic AMP. Am. J. Pathol. 81: 199-204
170. Abramson S. B. and Amin A. (2002) Blocking the effects of IL-1 in rheumatoid arthritis protects bone and cartilage. Rheumatology (Oxford) 41: 972-980
171. Barnette M. S. (1999) Phosphodiesterase 4 (PDE4) inhibitors in asthma and chronic obstructive pulmonary disease (COPD). Prog. Drug. Res. 53: 193-229
172. Essayan D. M. (1999) Cyclic nucleotide phosphodiesterase (PDE) inhibitors and immunomodulation. Biochem. Pharmacol. 57: 965-973
173. Dyke H. J. and Montana J. G. (1999) The therapeutic potemtial of PDE4 inhibitors. Expert Opin. Investig. Drugs 8: 1301-1325
174. Souness J. E. and Foster M. (1998) Potential of phosphodiesterse Type IV inhibitors in the treatment of rheumatoid arthritis. Idrugs 1: 541-553
175. Francischi J. N., Celina M. Y., Poole S., Tafuri W. L., Cunha F. Q. and Teixeira M. M. (2000) Anti-inflammatory analgesic effects of the phosphodiesterase 4 inhibitor rolipram in a rat model of arthritis. Eur. J. Pharmacol. 399: 243-249
176. Laemont K. D., Schaefer C. J., Juneau P. L. and Schrier D. J. (1999) Effects of the phosphodiesterse inhibitor rolipram on streptococcal cell wall-induced arthritis in rats. Int. J. Immunopharmacol. 21: 711-725
177. He W., Huang F. C. and Hanney B. (1998) Novel cyclic compounds as potent phosphodiesterase 4 inhibitors. J. Med. Chem. 41: 4216-4223
178. Mcgarry D. G., Regan J. R. and Volz F. A. (1999) Benzofuran based PDE4 inhibitors. Bioorg. Med. Chem. 7: 1131-1139
179. Manji H. K., Drevets W. C. and Charney D. S. (2001) The cellular neurobiology of depression. Nat. Med. Rev. 7: 541-547
180. Perez J., Tardito D., Racagni G., Smeraldi E. and Zanardi R. (2001) Protein kinase A and Rap1 levels in platelets of untreated patients with major depression. Mol. Psychiat. 6: 44-49
181. O'Donnell J. M. (1993) Antidepressant-like effects of rolipram and other inhibitors of cyclic adenosine monophosphate phosphodiesterase on behavior maintained by differential reinforcement of low response rate. J. Pharmacol. Exp. Ther. 264: 1168-1178
182. O'Donnell J. M., Frith S. and Wilkins J. (1994) Involvement of beta-1 and beta-2 adrenergic receptors in the antidepressantlike effects of centrally administered isoproterenol. J. Pharmacol. Exp. Ther. 271:246-254
183. O'Donnell J. M. and Frith S. A. (1999) Behavioral effects of family selective inhibitors of cyclic nucleotide phosphodiesterases. Pharmacol. Biochem. Behav. 63: 185-192
184. Zhang H. T., Frith S. A., Wilkins J. and O'Donnell J. M. (2001) Comparison of the effects of isoproterenol administered into the hippocampus, frontal cortex or amygdala on behavior of rats maintained by differential reinforcement of low response rate. Psychopharmacology (Berl) 159: 89-97
185. Houslay M. D. (2001) PDE4 cAMP-specific phosphodiesterases. Prog. Nucleic Acid Res. Mol. Biol. 69: 249-315
186. Zhang H. T. and O'Donnell J. M. (2000) Effects of rolipram on scopolamine-induced impairment of working and reference memory in the radial-arm maze tests in rats. Psychopharmacology (Berl) 150: 311-316
187. Zhang H. T., Crissman A. M., Dorairaj N. R., Chandler L. J. and O'Donnell J. M. (2000) Inhibition of cyclic AMP phosphodiesterase (PDE4) reverses memory deficits associated with NMDA receptor antagonism. Neuropsychopharmacology 23: 198-204
188. Ye Y. and O'Donnell J. M. (1996) Diminished noradrenergic stimulation reduces the activity of rolipram-sensitive, high-affinity cyclic AMP phosphodiesterase in rat cerebral cortex. J. Neurochem. 66: 1894-1902
189. Ye Y., Conti M., Houslay M. D., Farooqui S. M., Chen M. and O'Donnell J. M. (1997) Noradrenergic activity differentially regulates the expression of roliram-sensitive, high-affinity cycdlic AMP phosphodiesterase (PDE4) in rat brain. J. Neurochem. 69: 2397-2404
190. Cherry J. A. and Davis R. L. (1999) Cyclic AMP phosphodiesterases are localized in regions of the mouse brain associated with reinforcement, movement and affect. J. Comp. Neurol. 407: 287-301
191. Ye Y., Jackson K. and O'Donnell J. M. (2000) Effects of repeated antidepressant treatment of type 4A phosphodiesterase (PDE4A) in rat brain. J. Neurochem. 74: 1257-1262
192. Hansen G., Jin S., Umetsu D. T. and Conti M. (2000) Absence of muscarinic cholinergic airway responses in mice deficient in the cyclic nucleotide phosphodiesterase PDE4D. Proc. Natl. Acad. Sci. USA 97: 6751-6756
193. Jin S. L. C., Richard F. J., Kuo W. P., D'Ercole A. J. and Conti M. (1999) Impaired growth and fertility of cAMP-specific phosphodiesterase PDE4D-deficient mice. Proc. Natl. Acad. Sci. USA 96: 11998-12003
194. Keravis T., Komas N. and Lugnier C. (2000) Cyclic nucleotide hydrolysis in bovine aortic endothelial cells in culture: differential regulation in cobblestone and spindle phenotypes. J. Vasc. Res. 37: 235-349
195. Zhang H. T., Huang Y., Jin S. L. C., Frith S. A., Suvarna N., Conti M. et al. (2002) Antidepressant-like profile and reduced sensitivity to rolipram in mice deficient in the PDE4D phosphodiesterase enzyme. Neuropsychopharmacology 27: 587-595
196. Ghosh A., Carnahan J. and Greenberg M. E. (1994) Requirement for BDNF in activity-dependent survival of cortical neurons. Science 263: 1618-1623
197. Mamonous L. A., Blue M. E., Siuciak J. A. and Anthony Alter C. (1994) Brain-derived neurotrophic factor promotes the survival and sprouting of serotonergic axons in rat brain. J. Neurosci. 15: 1929-1939
198. Zafra F., Hengerer B., Thoenen H. and Lindholm D. (1990) Activity dependent regulation of BDNF and NGF mRNAs in the rat hippocampus is mediated by non-NMDA glutamate receptors. EMBO J. 11: 3545-3550
199. Zafra F., Lindholm D. and Thoenen H. (1992) Regulation of brain-derived neurotrophic factor and nerve growth factor mRNA in primary cultures of hippocampal neurons and astrocytes. J. Neurosci. 12: 4793-4799
200. Condorelli D. F., Dell'Albani P., Mudo G., Timmusk T. and Belluardo N. (1994) Expression of neurotrophins and their receptors in primary astroglial cultures: Induction by cAMP elevating agents. J. Neurochem. 63: 509-516
201. Nibuya M., Nestler E. J. and Duman R. S. (1996) Chronic antidepressant administration increases the expression of cAMP response element binding protein (CREB) in rat hippocampus. J. Neurosci. 16: 2365-2372
202. Nibuya M., Nestler E. J. and Duman R. S. (1996) Chronic antidepressant administration increases the expression of cAMP response element binding protein (CREB) in rat hippocampus. J. Neurosci. 16: 2365-2372
203. Fujimaki K., Morinobu S. and Duman R. S. (2000) Administration of a cAMP phosphodiesterase 4 inhibitor enhances antidepressant-induction of BDNF mRNA in rat hippocampus. Neuropsychopharmacology 22: 42-51
204. Beavo J. A. (1995) Cyclic nucleotide phosphodiesterase: functional implications of multiple isoforms. Physiol. Rev. 75:725-748
205. Francis S. H., Turko I. V. and Corbin J. D. (2001) Cyclic nucleotide phosphodiesterase: relating structure and function. Prog. Nucleic Acid Res. Mol. Biol. 65: 1-51
206. Reeves M. L., Leigh B. K. and England P. J. (1987) The identification of a new cyclic nucleotide phosphodiesterase activity in human and guinea-pig cardiac ventricle. Implications for the mechanism of action of selective phosphodiesterase inhibitors. Biochem. J. 241: 535-541
207. DiSanto M. E. and Heaslip R. J. (1995) Rolipram inhibition of phosphodiesterase-4 activation. Eur. J. Pharmacol. Mol. Pharmacol. 290: 169-172
208. Giembycz M. A. (2000) Phosphodiesterase 4 inhibitors and the treatment of asthma: Where are we now and where do we go from here? Drugs 59: 193-212
209. Hughes B., Owens R. J., Perry M. J., Warrellow G. and Allen R. (1997) PDE4 inhibitors: the use of molecular cloning in the design and development of novel drugs. DDT 2: 89-101
210. Souness J. E. and Rao S. (1997) Proposal for pharmacologically destruct conformers of the PDE4. Cell. Signal. 9: 227-236
211. Duplantier A. J., Biggers M. S., Chambers R. J., Cheng J. B., Cooper K. and Damon D. B. et al. (1996) Biarylcarboxylic acids and amides: inhibition of phosphodiesterase type IV versus [3H] rolipram binding activity and their relationship to emetic behavior in the ferret. J. Med. Chem. 39: 120-125
212. Torphy T. J., Barnette M. S., Underwood D. C., Griswold D. E., Christensen S. B., Murdoch R. D. et al. (1999) Ariflo (SB 207499), a second generation phosphodiesterase 4 inhibitor for the treatment of asthma and COPD: from concept to clinic. Pulm. Pharmacol. Ther. 12: 131-135
213. Hatzelmann A. and Schudt C. (2001) Anti-inflammatory and immunomodulatory potential of the novel PDE4 inhibitor roflumilast in vitro. J. Pharmacol. Exp. Ther. 297: 267-279
214. Baumer W., Gorr G., Hoppmann J., Ehinger A. M., Ehinger B. and Kietzmann M. (2002) Effects of the phosphodiesterase 4 inhibitors SB 207499 and AWD 12-281 on the inflammatory reaction in a model of allergic dermatitis. Eur. J. Pharmacol. 446: 195-200
215. Profita M., Chiappara G., Mirabella F., Di Giorgi R., Chimenti L., Costanzo G. et al. (2003) Effect of cilomilast (Ariflo) on TNF-alpha, IL-8 and GM-CSF release by airway cells of patients with COPD. Thorax 58: 573-579
216. Kohyama T., Liu X., Zhu Y. K., Wen F. Q., Wang H. J., Fang Q. et al. (2002) Phosphodiesterase 4 inhibitor cilomilast inhibits fibroblast-mediated collagen gel degradation induced by tumor necrosis factor-alpha and neutrophil elastase. Am. J. Respir. Cell Mol. Biol. 27: 487-494
217. Kohyama T., Liu X., Wen F. Q., Zhu Y. K., Wang H., Kim H. J. et al. (2002) PDE4 inhibitors attenuate fibroblast chemotaxis and contraction of native collagen gels. Am. J. Respir. Cell Mol. Biol. 26: 694-701
218. Antonio A. M. and Vignola M. (2004) PDE4 inhibitors in COPD - a more selective approach to treatment. Respir Med. 98(6): 495-503
219. IDDB database, 22-SMI conference on asthma therapeutics, 2003, London
220. Altana A. G., press release, 11 Sep., 2003
221. Altana A. G., press release, 23 Sep., 2003
222. SMI conference on anti-inflammatory therapeutics, 2003, London
223. Uchida E., Chou T., Hukazawa I., Nagumo A. and Yasuda K. (1995) Safety and pharmacokinetics of DO-309 in healthy volunteers: repeated oral administration. Japanese Journal of Clinical Pharmacology and Therapeutics 26: 857-866
224. Cazzola M., Donner C. F. and Matera M. G. (1999) Long acting beta-2 agonists and theophylline in stable chronic obstructive pulmonary disease. Thorax 54: 730-736
225. Barnes P. J. (2003) Theophylline: new perspectives for an old drug. Am. J. Respir. Crit. Care Med. 167: 813-818
226. Dent G. and Giembycz M. A. (1996) Phosphodiesterase inhibitors: lily the pink's medicinal compound for asthma? Thorax 51: 647-649
227. Corbin J. D., Turko I. V., Reasly A. and Francis S. H. (2000) Phosphorylation of phosphodiesterase-5 by cyclic nucleotide dependent protein kinase alters its catalytic and allosteric cGMP binding affinitys. Eur. J. Biochem. 267: 2760-2767
228. Rotella D. P. (2002) Phosphodiesterase 5 inhibitors: current status and potential applications. Nat. Rev. Drug Discov. 1: 674-684
229. Yanaka N. (1998) Expression, structure and chromosomal localization of the human cGMP-binding, cGMP specific phsphodiesterase PDE5 gene. Eur. J. Biochem. 255: 391-399
230. Rosen R. and Mckenna K. (2003) PDE-5 inhibition and sexual responses: pharmacological mechanism and clinical outcomes. Annu. Rev. Sex Res. 13: 36-88
231. Goldstein I., Lue T. F. and Padma-Nathan H. (1998) Oral sildenafil in the treatment of erectile dysfunction. N. Engl. J. Med. 338: 1397-1404
232. Rosenberg K. P. (1999) Sildenafil citrate for SSRI-induced sexual side effects. Am. J. Psychiatry 156: 157
233. Briganti A., Salonia A., Gallina A., Suardi N., Riggati P. and Montorsi F. (2004) Emerging oral drug for erectile dysfunction. Expert Opin. Emerg. Drugs 9: 179-189
234. Kloner R. A., Brown M., Prisant L. M. and Collins M. (2001) Effect of sildenafil in patients with erectile dysfunction taking antihypertensive therapy. Am. J. Hypertens. 14: 70-73
235. Conti R. C., Pepine C. J. and Sweeney M. (1999) Efficacy and safety of sildenafil citrate in the treatment of erectile dysfunction in patients with ischemic heart disease. Am. J. Cardiol. 83: 29C-34C
236. Angulo J., Gadau M. and Fernandez A. (2001) IC351 enhances NO-mediated relaxation of human arterial and trabecular penile smooth muscle. Eur. Urol. 39: 106 (Abstract 415)
237. Padma-Nathan H., Rosen R. C., Shobsigh R., Watkins V. S. and Pullman B. (2001) Cialis (IC351) provides prompt response and extended responsiveness for the treatment of erectile dysfunction. J. Urol. 165: 224
238. Porst H. (2002) IC351 (tadalafil, Cialis): update on clinical experience. Int. J. Impotence Res. 14 (Suppl. 1): S57-S64
239. Hutter A. M. (2002) Blood pressure and cardiovascular effects of tadalafil, a new PDE5 inhibitor. Am. J. Hypertens. 15 (Part 2): 140A
240. Padma-Nathan H. (2002) Efficacy and safety of tadalafil in men with erectile dysfunction with and without hypertension. Am. J. Hypertens. 15 (Part 2): 143A
241. Stark S., Sachse R. and Liedl T. (2001) Vardenafil increased penile rigidity and tumescence in men with erectile dysfunction after single oral dose. Eur. Urol. 40: 181-190
242. Klotz T., Sachse R. and Heidrich A. (2001) Vardenafil increased penile rigidity and tumescence in erectile dysfunction patients: a RigiScan and pharmacokinetic study. World J. Urol. 19: 32-39
243. Vardenafil effective and safe as ED therapy in men with prostatectomy, CAD and hypertension. Prous Daily Essentials, 27 February 2002
244. Movsesian M. A. and Alharethi R. (2002) Inhibitors of cyclic nucleotide phosphodiesterase PDE3 as adjunct therapy for dilated cardiomyopathy. Expert Opin. Investig. Drugs 11: 1529-1536
245. Fleming J. S. and Buyniski J. P. (1979) A potent new inhibitor of platelet aggregation and experimental thrombosis, anagrelide (BL-4162A). Thromb. Res. 15: 373-388
246. Packer M., Carver J. R. and Rodeheffer R. J. (1991) Effect of oral milrinone on mortality in severe chronic heart failure. The PROMISE Study Research Group. N. Engl. J. Med. 325: 1468-1475
247. Nony P., Boissel J. P. and Lirvre M. (1994) Evaluation of the effect of phosphodiesterase inhibitors on mortality in chronic heart failure patients. A metaanalysis. Eur. J. Clin. Pharmacol. 46: 191-196
248. Feldman A. M., Bristow M. R. and Parmley W. W. (1993) Effects of vesnarinone on morbidity and mortality in patients with heart failure. Vesnarinone Study Group. N. Engl. J. Med. 329: 149-155
249. Cohn J. N., Goldstein S. O. and Greenberg B. H. (1998) A dose-dependent increase in mortality with vesnarinone among patients with severe heart failure. Vesnarinone Trial Investigators. N. Engl. J. Med. 339: 1810-1816
250. Uretsky B. F., Jessup M. and Konstam M. A. (1990) Multicenter trial of oral enoximone in patients with moderate to moderately severe congestive heart failure. Lack of benefit compared with placebo. Enoximone Multicenter Trial Group. Circulation 82: 774-780
251. Ross R. (1999) Atherosclerosis - an inflammatory disease. N. Engl. J. Med. 340: 115-126
252. Matsumoto T., Kogayashi T. and Kamata K. (2003) Phosphodiesterases in the vascular system. J. Smooth Muscle Res. 39 (4): 67-86
253. Vemulapalli S., Watkins R. W. and Chintala M. (1996) Anti-platelet and antiproliferative effects of SCH 51866 a novel type I and V phosphodiesterase inhibitor. Cardiovasc. Pharmacol. 28: 862-869
254. Perry M. J. and Higgs G. A. (1998) Chemotherapeutic potential of phosphodiesterase inhibitors. Curr. Opin. Chem. Biol. 2: 472-481