Rolipram

From Wikipedia, the free encyclopedia
Jump to: navigation, search
Rolipram
RolipramRacemate2DACS2.svg
Rolipram3Dan2.gif
Systematic (IUPAC) name
(RS)-4-(3-cyclopentyloxy-4-methoxy-phenyl)pyrrolidin-2-one
Clinical data
Legal status Investigational
Pharmacokinetic data
Bioavailability 75%[1]
Metabolism Hepatic via CYP2C8, CYP2C9, CYP2C19 and CYP2D6[1]
Half-life 3 hours[1]
Excretion Urine (80%)[1]
Identifiers
CAS number 61413-54-5 YesY
87714-57-6[citation needed]
ATC code None
PubChem CID 5092
DrugBank DB04149
ChemSpider 4913 YesY
UNII K676NL63N7 YesY
ChEBI CHEBI:104872 YesY
ChEMBL CHEMBL63 YesY
Chemical data
Formula C16H21NO3 
Mol. mass 275.347 g/mol
 N (what is this?)  (verify)

Rolipram is a racetam and a selective phosphodiesterase-4 inhibitor, which particularly targets the PDE4B subtype of phosphodiesterase 4.[2] Like most PDE4-inhibitors, it is an anti-inflammatory drug.[3] Rolipram has been studied as a possible antidepressant.[2][4][5] Rolipram also has anti-inflammatory,[6] immunosuppressive,[6] and anti-tumor effects.[7][8] Rolipram has also been proposed as a treatment for multiple sclerosis.[9] Recent studies show that rolipram may have antipsychotic effects.[10][11] Other beneficial effects of rolipram in animal experiments are:

  • Improved long term memory[12]
  • Increased wakefulness[13]
  • Increased neuroprotection[14][15]
  • In animal studies: promotion of axonal regeneration and functional recovery from spinal cord lesions [16]

Animal studies of rolipram show promise in ameliorating Alzheimer's disease,[17] Parkinson's disease [18] and also in the regeneration of severed spinal cord axonal bodies.[19]

Side effects[edit]

Rolipram is characterized for its emetic and other problematic effects.[20] In this regard, it compares unfavorably to another PDE4-inhibitor, GEBR-7b, whose effect on memory was 3 to 10 times more potent than that of rolipram, and its effective doses had no effect on surrogate measures of emesis in rodents.[21]

The R(-) enantiomer is the active enantiomer.[1]

References[edit]

  1. ^ a b c d e Krause, W; Kühne, G; Sauerbrey, N (1990). "Pharmacokinetics of (+)-rolipram and (-)-rolipram in healthy volunteers" (PDF). European Journal of Clinical Pharmacology 38 (1): 71–75. doi:10.1007/BF00314807. PMID 2328751. 
  2. ^ a b Zhu, J; Mix, E; Winblad, B (Winter 2001). "The antidepressant and antiinflammatory effects of rolipram in the central nervous system.". CNS Drug Reviews 7 (4): 387–98. PMID 11830756. 
  3. ^ Griswold, DE; Webb, EF; Breton, J; White, JR; Marshall, PJ; Torphy, TJ (1993). "Effect of selective phosphodiesterase type IV inhibitor, rolipram, on fluid and cellular phases of inflammatory response". Inflammation 17 (3): 333–44. doi:10.1007/BF00918994. PMID 7687237. 
  4. ^ Bobon, D; Breulet, M; Gerard-Vandenhove, MA; Guiot-Goffioul, F; Plomteux, G; Sastre-y-Hernandez, M; Schratzer, M; Troisfontaines, B; von Frenckell, R; Wachtel, H (1988). "Is phosphodiesterase inhibition a new mechanism of antidepressant action? A double blind double-dummy study between rolipram and desipramine in hospitalized major and/or endogenous depressives". Eur Arch Psychiatry Neurol Sci 238 (1): 2–6. doi:10.1007/BF00381071. PMID 3063534. 
  5. ^ Wachtel, H (1983). "Potential antidepressant activity of rolipram and other selective cyclic adenosine 3',5'-monophosphate phosphodiesterase inhibitors". Neuropharmacology 22 (3): 267–72. doi:10.1016/0028-3908(83)90239-3. PMID 6302550. 
  6. ^ a b Sommer, N; Löschmann, PA; Northoff, GH; Weller, M; Steinbrecher, A; Steinbach, JP; Lichtenfels, R; Meyermann, R; Riethmüller, A; Fontana, A (March 1995). "The antidepressant rolipram suppresses cytokine production and prevents autoimmune encephalomyelitis.". Nature Medicine 1 (3): 244–8. doi:10.1038/nm0395-244. PMID 7585041. 
  7. ^ Chen, TC; Wadsten, P; Su, S; Rawlinson, N; Hofman, FM; Hill, CK; Schönthal, AH (May–June 2002). "The type IV phosphodiesterase inhibitor rolipram induces expression of the cell cycle inhibitors p21(Cip1) and p27(Kip1), resulting in growth inhibition, increased differentiation, and subsequent apoptosis of malignant A-172 glioma cells.". Cancer biology & therapy 1 (3): 268–76. PMID 12432276. 
  8. ^ Semmler, J; Wachtel, H; Endres, S (April 1993). "The specific type IV phosphodiesterase inhibitor rolipram suppresses tumor necrosis factor-alpha production by human mononuclear cells.". International journal of immunopharmacology 15 (3): 409–13. doi:10.1016/0192-0561(93)90052-z. PMID 8505151. 
  9. ^ Mendes, E; Wadsten, P; Su, S; Rawlinson, N; Hofman, FM; Hill, CK; Schönthal, AH (November 1975). "Immunological studies on bronchial secretion. I. Antigenic relationship between bronchial secretion and serum: bronchial secretion constituents detected in human sera.". Acta allergologica 30 (5): 259–66. doi:10.1111/j.1398-9995.1975.tb00202.x. PMID 12432276. 
  10. ^ Maxwell, CR; Kanes, SJ; Abel, T; Siegel, SJ (2004). "Phosphodiesterase inhibitors: a novel mechanism for receptor-independent antipsychotic medications". Neuroscience 129 (1): 101–7. doi:10.1016/j.neuroscience.2004.07.038. PMID 15489033. 
  11. ^ Kanes, SJ; Tokarczyk, J; Siegel, SJ; Bilker, W; Abel, T; Kelly, MP (2006). "Rolipram: A specific phosphodiesterase 4 inhibitor with potential antipsychotic activity". Neuroscience 144 (1): 239–46. doi:10.1016/j.neuroscience.2006.09.026. PMC 3313447. PMID 17081698. 
  12. ^ Barad, M; Bourtchouladze, R; Winder, DG; Golan, H; Kandel, E (1998). "Rolipram, a type IV-specific phosphodiesterase inhibitor, facilitates the establishment of long-lasting long-term potentiation and improves memory". Proceedings of the National Academy of Sciences of the United States of America 95 (25): 15020–5. doi:10.1073/pnas.95.25.15020. PMC 24568. PMID 9844008. 
  13. ^ Lelkes, Z; Alföldi, P; Erdos, A; Benedek, G (1998). "Rolipram, an antidepressant that increases the availability of cAMP, transiently enhances wakefulness in rats". Pharmacology, Biochemistry and Behaviour 60 (4): 835–9. doi:10.1016/S0091-3057(98)00038-0. PMID 9700966. 
  14. ^ Block, F; Schmidt, W; Nolden-Koch, M; Schwarz, M (2001). "Rolipram reduces excitotoxic neuronal damage". NeuroReport 12 (7): 1507–11. doi:10.1097/00001756-200105250-00041. PMID 11388438. 
  15. ^ Chen, RW; Williams, AJ; Liao, Z; Yao, C; Tortella, FC; Dave, JR (2007). "Broad spectrum neuroprotection profile of phosphodiesterase inhibitors as related to modulation of cell-cycle elements and caspase-3 activation". Neuroscience Letters 418 (2): 165–9. doi:10.1016/j.neulet.2007.03.033. PMID 17398001. 
  16. ^ Nikulina, E; Tidwell, JL; Dai, HN; Bregman, BS; Filbin, MT (published ahead of print June 1, 2004). "The phosphodiesterase inhibitor rolipram delivered after a spinal cord lesion promotes axonal regeneration and functional recovery". Proceedings of the National Academy of Sciences 101 (23): 8786. doi:10.1073/pnas.0402595101. Retrieved 2012-10-13. 
  17. ^ Smith, DL; Pozueta, J; Gong, B; Arancio, O; Shelanski, M (September 2009). "Reversal of long-term dendritic spine alterations in Alzheimer disease models". Proceedings of the National Academy of Sciences of the United States of America 106 (39): 16877–16882. doi:10.1073/pnas.0908706106. PMC 2743726. PMID 19805389. Retrieved 2009-11-13. 
  18. ^ MF, Beal; Cleren C, Calingasan NY, Yang L, Klivenyi P, Lorenzl S (2005). "Oxidative Damage in Parkinson's Disease". U.S. Army Medical Research and Materiel CommandFort Detrick, Maryland 21702-5012. Retrieved 2009-11-13. 
  19. ^ Nikulina, E (June 8, 2004). "The Phosphodiesterase Inhibitor Rolipram Delivered after a Spinal Cord Lesion Promotes Axonal Regeneration and Functional Recovery". Proceedings of the National Academy of Sciences of the United States of America 101 (23): 8786. doi:10.1073/pnas.0402595101. JSTOR 3372336. 
  20. ^ Heaslip, RJ; Evans, DY (November 1995). "Emetic, central nervous system, and pulmonary activities of rolipram in the dog". European Journal of Pharmacology 286 (3): 281–290. doi:10.1016/0014-2999(95)00457-2. PMID 8608790. 
  21. ^ Bruno, O; Fedele, E; Prickaerts, J; Parker, LA; Canepa, E; Brullo, C; Cavallero, A; Gardella, E; Balbi, A; Domenicotti, C; Bollen, E; Gijselaers, HJ; Vanmierlo, T; Erb, K; Limebeer, CL; Argellati, F; Marinari, UM; Pronzato, MA; Ricciarelli, R (December 2011). "GEBR-7b, a novel PDE4D selective inhibitor that improves memory in rodents at non-emetic doses" (PDF). British Journal of Pharmacology 164 (8): 2054–2063. doi:10.1111/j.1476-5381.2011.01524.x. PMC 3246667. PMID 21649644.