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Hanting Zhang - One of the best experts on this subject based on the ideXlab platform.
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Antidepressant-like effects of PDE4 Inhibitors mediated by the high-affinity rolipram binding state (HARBS) of the phosphodiesterase-4 enzyme (PDE4) in rats
Psychopharmacology, 2006Co-Authors: Hanting Zhang, Ying Huang, Chengjun Deng, Allen T Hopper, Michael De Vivo, Gregory M Rose, Yu Zhao, James M. O’donnellAbstract:Rationale Phosphodiesterase-4 (PDE4) has two conformation states based on rolipram binding, the high-affinity rolipram binding state (HARBS) and the low-affinity rolipram binding state (LARBS); their functions remain to be fully explained. Objective Experiments were carried out to determine the roles of the HARBS and LARBS in the mediation of antidepressant-like effects on behavior. Materials and methods Two animal models sensitive to antidepressant drugs, the forced-swim test (FST), and the differential-reinforcement-of-low-rate (DRL) 72-s operant schedule, were used to examine the antidepressant-like effects of rolipram, CDP840, and piclamilast, PDE4 Inhibitors that interact differentially with the HARBS and LARBS, and MEM1018 and MEM1091, two novel PDE4 Inhibitors. Drug discrimination vs rolipram and rolipram competition binding assays also were carried out. Results In the FST, rolipram and piclamilast, both at 0.1 mg/kg, produced an antidepressant-like effect, i.e., reduced immobility and increased swimming, whereas, 1 mg/kg of CDP840 or 0.5 mg/kg of MEM1018 or MEM1091 was required to produce a similar effect. Consistent with this, only rolipram and piclamilast produced antidepressant-like effects in rats under the DRL schedule of reinforcement, as evidenced by decreased response rates and increased reinforcement rates. In addition, in rats trained to discriminate rolipram from its vehicle, only rolipram and piclamilast substituted. Finally, [^3H]rolipram and [^3H]piclamilast binding analysis revealed that CDP840 and the two novel PDE4 Inhibitors MEM1018 and MEM1091 exhibited a lower affinity for the HARBS than did rolipram. Conclusion These results suggest that the HARBS of PDE4 is the primary conformation important for antidepressant-like effects on behavior.
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Effects of the novel PDE4 Inhibitors MEM1018 and MEM1091 on memory in the radial-arm maze and inhibitory avoidance tests in rats
Psychopharmacology, 2005Co-Authors: Hanting Zhang, Ying Huang, Neesha U Suvarna, Chengjun Deng, Alicia M Crissman, Allen T Hopper, Michael De Vivo, Gregory M Rose, James M. O’donnellAbstract:Rationale Inhibition of cyclic AMP (cAMP)-specific phosphodiesterase (PDE4) enhances memory in rodents. MEM1018 and MEM1091 are newly developed PDE4 Inhibitors that had not been evaluated as yet for their effects on working and reference memory. Objective Experiments were carried out to determine whether these two drugs alter memory and if these effects are associated with changes in intracellular cAMP in the brain. Methods The effects of MEM1018 and MEM1091 on memory deficits induced by the N -methyl- d- aspartate (NMDA) receptor antagonist MK-801 were determined in the eight-arm radial maze and step-through inhibitory avoidance tasks in rats. Their effects on cAMP concentrations in primary cultures of rat cerebral cortical neurons and their potency for inhibiting recombinant PDE4 subtypes were examined. Results In the radial-arm maze, MEM1018 and MEM1091 (0.1–2.5 mg/kg, IP) enhanced working and reference memory impaired by MK-801 (0.1 mg/kg). In addition, both drugs antagonized the amnesic effect of MK-801 on passive avoidance behavior. Overall, the behavioral effects of MEM1018 and MEM1091 were similar to the prototypic PDE4 inhibitor rolipram (0.1 mg/kg). Consistent with this, and similar to the effects of rolipram, both MEM1018 (10–30 μM) and MEM1091 (10 μM) enhanced the ability of NMDA (30 μM) to increase cAMP concentrations in rat cerebral cortical neurons, in vitro. MEM1018 and MEM1091 showed greater relative selectivity for PDE4D than rolipram, although the general profiles of the three compounds were similar. Conclusions The novel PDE4 Inhibitors MEM1018 and MEM1091 enhance memory in a manner generally similar to rolipram. PDE4D may be the primary target for the PDE4 Inhibitors in the mediation of memory.
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effects of the novel PDE4 Inhibitors mem1018 and mem1091 on memory in the radial arm maze and inhibitory avoidance tests in rats
Psychopharmacology, 2005Co-Authors: Hanting Zhang, Ying Huang, Neesha U Suvarna, Chengjun Deng, Alicia M Crissman, Allen T Hopper, Michael De Vivo, Gregory M Rose, James M OdonnellAbstract:Rationale Inhibition of cyclic AMP (cAMP)-specific phosphodiesterase (PDE4) enhances memory in rodents. MEM1018 and MEM1091 are newly developed PDE4 Inhibitors that had not been evaluated as yet for their effects on working and reference memory.
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antidepressant effects of Inhibitors of camp phosphodiesterase PDE4
Trends in Pharmacological Sciences, 2004Co-Authors: James M Odonnell, Hanting ZhangAbstract:Abstract Despite initial promise, the development of type 4 phosphodiesterase (PDE4) Inhibitors as antidepressants has not advanced significantly. This is due to an incomplete understanding of the functional importance of PDE4 subtypes and high-affinity and low-affinity inhibitor-binding conformers. However, recent developments have rekindled interest in the therapeutic potential of PDE4 Inhibitors. First, PDE4 has been shown to be involved in cAMP signaling pathways that are affected by antidepressants. Second, data obtained using mouse knockout lines indicate that PDE4D and PDE4B mediate antidepressant effects. Third, it appears that the interaction of Inhibitors with the high-affinity binding conformer of PDE4 is particularly important for antidepressant efficacy. These developments highlight the difficulties of dissociating the actions of PDE4 Inhibitors and provide a guide for future research.
Mark A. Giembycz - One of the best experts on this subject based on the ideXlab platform.
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can the anti inflammatory potential of PDE4 Inhibitors be realized guarded optimism or wishful thinking
British Journal of Pharmacology, 2009Co-Authors: Mark A. GiembyczAbstract:PDE4 Inhibitors have been in development as a novel anti-inflammatory therapy since the 1980s with asthma and chronic obstructive pulmonary disease (COPD) being primary indications. Despite initial optimism, none have yet reached the market. In most cases, the development of PDE4 Inhibitors of various structural classes, including cilomilast, filaminast, lirimilast, piclamilast, tofimilast, AWD-12-281 (aka GSK 842470), CDP840, CI-1018, D-4418, IC485, L-826,141, SCH 351391 and V11294A has been discontinued due to lack of efficacy. A primary problem is the low therapeutic ratio of these compounds, which severely limits the dose that can be given. Indeed, for many of these compounds it is likely that the maximum tolerated dose is either sub-therapeutic or at the very bottom of the efficacy dose-response curve. Therefore, the challenge is to overcome this limitation. It is, therefore, encouraging that many ‘new(er)' PDE4 Inhibitors in development are reported to have an improved therapeutic window including tetomilast, oglemilast, apremilast, ONO 6126, IPL-512602 and IPL-455903 (aka HT-0712), although the basis for their superior tolerability has not been disclosed. In addition, other approaches are possible that may allow the anti-inflammatory activity of PDE Inhibitors to be realized. Accordingly, this Commentary endorses the view of Spina (2008), published in the current issue of the British Journal of Pharmacology, that the therapeutic utility of PDE4 Inhibitors to suppress inflammation still remains a viable concept.
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Can the anti‐inflammatory potential of PDE4 Inhibitors be realized: guarded optimism or wishful thinking?
British Journal of Pharmacology, 2008Co-Authors: Mark A. GiembyczAbstract:PDE4 Inhibitors have been in development as a novel anti-inflammatory therapy since the 1980s with asthma and chronic obstructive pulmonary disease (COPD) being primary indications. Despite initial optimism, none have yet reached the market. In most cases, the development of PDE4 Inhibitors of various structural classes, including cilomilast, filaminast, lirimilast, piclamilast, tofimilast, AWD-12-281 (aka GSK 842470), CDP840, CI-1018, D-4418, IC485, L-826,141, SCH 351391 and V11294A has been discontinued due to lack of efficacy. A primary problem is the low therapeutic ratio of these compounds, which severely limits the dose that can be given. Indeed, for many of these compounds it is likely that the maximum tolerated dose is either sub-therapeutic or at the very bottom of the efficacy dose-response curve. Therefore, the challenge is to overcome this limitation. It is, therefore, encouraging that many ‘new(er)' PDE4 Inhibitors in development are reported to have an improved therapeutic window including tetomilast, oglemilast, apremilast, ONO 6126, IPL-512602 and IPL-455903 (aka HT-0712), although the basis for their superior tolerability has not been disclosed. In addition, other approaches are possible that may allow the anti-inflammatory activity of PDE Inhibitors to be realized. Accordingly, this Commentary endorses the view of Spina (2008), published in the current issue of the British Journal of Pharmacology, that the therapeutic utility of PDE4 Inhibitors to suppress inflammation still remains a viable concept.
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4D or not 4D - the emetogenic basis of PDE4 Inhibitors uncovered?
Trends in Pharmacological Sciences, 2002Co-Authors: Mark A. GiembyczAbstract:Compelling evidence supports the idea that phosphodiesterase (PDE) 4 Inhibitors have utility in the treatment of airways inflammatory diseases such as asthma and chronic obstructive pulmonary disease (COPD). However, most PDE4 Inhibitors tested in clinical trials have, so far, exhibited a low therapeutic ratio, and side-effects including nausea and vomiting are common and potentially worrisome. These adverse events result from the inhibition of PDE4 in the gut and brain and, although the therapeutic ratio of second-generation PDE4 Inhibitors has been improved by targeting a conformation of PDE4 that is abundant in pro-inflammatory and immune cells, untoward effects still preclude their administration at doses necessary for optimal clinical activity to be realised.Now, Robichaud and colleagues [1xDeletion of phosphodiesterase 4D in mice shortens α2-adrenoceptor-mediated anesthesia: a behavioural surrogate of emesis. Robichaud, A. et al. J. Clin. Invest. 2002; 110: 1045–1052Crossref | PubMedSee all References][1] provide evidence that emesis resulting from administration of PDE4 Inhibitors is due to the selective inhibition of PDE4D, one of four PDE4 gene families that is enriched in the brainstem. This is an unfortunate finding because the most clinically advanced PDE4 Inhibitors are selective for PDE4D. Nevertheless, the data readily account for the poor tolerability of these compounds in clinical trials. To understand how this discovery was made, an understanding of α2-adrenoceptor-mediated anaesthesia is required. The hypnotic action of drugs such as xylazine, an α2-adrenoceptor agonist, is exerted at the locus coeruleus, a nucleus within the brainstem from which ascending and descending noradrenergic fibres originate to innervate the CNS. Activation of these α2-adrenoceptors at presynaptic sites is thought to inhibit adenylyl cyclase and reduce the intracellular levels of cAMP, leading, ultimately, to a state of anaesthesia. In a previous publication [2xPDE4 Inhibitors induce emesis in ferrets via a noradrenergic pathway. Robichaud, A. Neuropharmacology. 2001; 40: 262–269Crossref | PubMed | Scopus (83)See all References][2] the same investigators showed that PDE4 Inhibitors activate the vomiting reflex in ferrets through a sympathetic pathway by mimicking the pharmacological actions of yohimbine, an α2-adrenoceptor antagonist. Moreover, emesis was prevented in animals given the α2-adrenoceptor agonist clonidine [2xPDE4 Inhibitors induce emesis in ferrets via a noradrenergic pathway. Robichaud, A. Neuropharmacology. 2001; 40: 262–269Crossref | PubMed | Scopus (83)See all References][2]. Thus, the ability of PDE4 Inhibitors to reverse xylazine-induced anaesthesia represents a behavioural surrogate index of their emetic potential that can be used in non-vomiting species.Robichaud and co-workers have exploited this phenomenon by using mice deficient in either the PDE4B or PDE4D gene and provide four lines of evidence linking emesis with the inhibition of PDE4D. First, the duration of xylazine-induced anaesthesia in PDE4D knockout mice was significantly shorter compared with wild-type littermates, whereas the anaesthetic affected PDE4B-deficient and wild-type mice to the same degree. Second, a PDE4 inhibitor significantly reduced the duration of anaesthesia in wild-type mice but not in animals lacking PDE4D. Third, PDE4 activity in the brainstem of PDE4D knockout mice was markedly lower compared with wild-type and PDE4B-deficient animals, indicating that PDE4D is the principle regulator of cAMP metabolism in this brain structure. Forth, emesis was related to the ability of PDE4 Inhibitors to penetrate the CNS rather than their affinity for PDE4.Collectively, these data provide a rational scientific explanation of PDE4-inhibitor-induced emesis and a basis upon which to develop non-emetic compounds. However, several crucial questions still remain. Does inhibition of PDE4D promote emesis in humans? Can PDE4A and/or PDE4C regulate emesis? A contention formulated over recent years is that the emetogenicity of PDE4 Inhibitors relates to the inhibition of a conformation of PDE4, the so-called high-affinity rolipram-binding site, which is enriched in the brain. Does this idea still hold or were the observations upon which this hypothesis is formulated purely fortuitous? Does selective inhibition of PDE4A, B or C exert anti-inflammatory and/or immunomodulatory activity? Do PDE4 Inhibitors need to inhibit PDE4D for inflammatory activity to be realised? Answers to some of these questions are beginning to emerge. Evidence to date suggests that selective Inhibitors of PDE4A and/or PDE4B should have a much improved therapeutic ratio compared with currently used PDE4 Inhibitors and could have significant therapeutic utility in inflammatory diseases, such as COPD, that respond poorly to steroids.
Hazel Joan Dyke - One of the best experts on this subject based on the ideXlab platform.
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8 methoxyquinolines as PDE4 Inhibitors
Bioorganic & Medicinal Chemistry Letters, 2002Co-Authors: Motasim M Billah, Hazel Joan Dyke, George M. Buckley, Nicola Cooper, Lewis Gowers, Hannah Jayne Kendall, Robert W Egan, Ashit K Ganguly, Alan Findlay Haughan, Christopher R LoweAbstract:The synthesis and pharmacological profile of a novel series of 2-substituted 8-methoxyquinolines is described. The 2-trifluoromethyl compound was found to be a potent inhibitor of phosphodiesterase type 4 (PDE4).
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Update on the therapeutic potential of PDE4 Inhibitors.
Expert Opinion on Investigational Drugs, 2002Co-Authors: John Gary Montana, Hazel Joan DykeAbstract:Phosphodiesterase (PDE) enzymes are responsible for the inactiviation of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Phosphodiesterase 4 (PDE4) is a cAMP specific phosphodiesterase expressed in inflammatory cells such as eosinophils. Inhibition of PDE4 results in an elevation of cAMP in these cells, which in turn downregulates the inflammatory response. The anti-inflammatory effects of PDE4 Inhibitors have been well documented both in vitro and in vivo in a range of animal models. The potential use of PDE4 Inhibitors as anti-inflammatory agents for the treatment of diseases such as asthma, chronic obstructive pulmonary disease (COPD) and multiple sclerosis (MS), has received considerable attention from the pharmaceutical industry but to date, there are no selective PDE4 Inhibitors on the market. Early PDE4 Inhibitors, such as rolipram suffered from dose limiting side effects, including nausea and emesis, which severely restricted their therapeutic utility. Second gener...
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the therapeutic potential of PDE4 Inhibitors
Expert Opinion on Investigational Drugs, 1999Co-Authors: Hazel Joan Dyke, John Gary MontanaAbstract:Phosphodiesterase enzymes are responsible for the inactivation of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Phosphodiesterase 4 (PDE4) is a cAMP specific phos...
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Aryl sulfonamides as selective PDE4 Inhibitors
Bioorganic & Medicinal Chemistry Letters, 1998Co-Authors: John Gary Montana, Hazel Joan Dyke, George M. Buckley, Nicola Cooper, Lewis Gowers, Joanna P Gregory, Paul G. Hellewell, Hannah Jayne Kendall, Christopher Lowe, Robert James MaxeyAbstract:A series of novel selective phosphodiesterase 4 (PDE4) Inhibitors has been developed which displays activity both in vitro and in vivo. These compounds possess good selectivity for the catalytic site of PDE4 over the high affinity Rolipram binding site. In vivo studies demonstrate a reduced propensity to display the emetic side effects which are commonly observed with PDE4 Inhibitors.
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PDE4 Inhibitors: New xanthine analogues
Bioorganic & Medicinal Chemistry Letters, 1998Co-Authors: John Gary Montana, Hazel Joan Dyke, Nicola Cooper, Lewis Gowers, Joanna P Gregory, Paul G. Hellewell, Jadwiga Miotla, Ken Morris, Robert J. Naylor, B. R. TuladharAbstract:Novel xanthine analogues are described which are selective PDE4 Inhibitors with improved therapeutic potential over theophylline.
John Gary Montana - One of the best experts on this subject based on the ideXlab platform.
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Update on the therapeutic potential of PDE4 Inhibitors.
Expert Opinion on Investigational Drugs, 2002Co-Authors: John Gary Montana, Hazel Joan DykeAbstract:Phosphodiesterase (PDE) enzymes are responsible for the inactiviation of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Phosphodiesterase 4 (PDE4) is a cAMP specific phosphodiesterase expressed in inflammatory cells such as eosinophils. Inhibition of PDE4 results in an elevation of cAMP in these cells, which in turn downregulates the inflammatory response. The anti-inflammatory effects of PDE4 Inhibitors have been well documented both in vitro and in vivo in a range of animal models. The potential use of PDE4 Inhibitors as anti-inflammatory agents for the treatment of diseases such as asthma, chronic obstructive pulmonary disease (COPD) and multiple sclerosis (MS), has received considerable attention from the pharmaceutical industry but to date, there are no selective PDE4 Inhibitors on the market. Early PDE4 Inhibitors, such as rolipram suffered from dose limiting side effects, including nausea and emesis, which severely restricted their therapeutic utility. Second gener...
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the therapeutic potential of PDE4 Inhibitors
Expert Opinion on Investigational Drugs, 1999Co-Authors: Hazel Joan Dyke, John Gary MontanaAbstract:Phosphodiesterase enzymes are responsible for the inactivation of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Phosphodiesterase 4 (PDE4) is a cAMP specific phos...
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Aryl sulfonamides as selective PDE4 Inhibitors
Bioorganic & Medicinal Chemistry Letters, 1998Co-Authors: John Gary Montana, Hazel Joan Dyke, George M. Buckley, Nicola Cooper, Lewis Gowers, Joanna P Gregory, Paul G. Hellewell, Hannah Jayne Kendall, Christopher Lowe, Robert James MaxeyAbstract:A series of novel selective phosphodiesterase 4 (PDE4) Inhibitors has been developed which displays activity both in vitro and in vivo. These compounds possess good selectivity for the catalytic site of PDE4 over the high affinity Rolipram binding site. In vivo studies demonstrate a reduced propensity to display the emetic side effects which are commonly observed with PDE4 Inhibitors.
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PDE4 Inhibitors: New xanthine analogues
Bioorganic & Medicinal Chemistry Letters, 1998Co-Authors: John Gary Montana, Hazel Joan Dyke, Nicola Cooper, Lewis Gowers, Joanna P Gregory, Paul G. Hellewell, Jadwiga Miotla, Ken Morris, Robert J. Naylor, B. R. TuladharAbstract:Novel xanthine analogues are described which are selective PDE4 Inhibitors with improved therapeutic potential over theophylline.
James M. O’donnell - One of the best experts on this subject based on the ideXlab platform.
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Antidepressant-like effects of PDE4 Inhibitors mediated by the high-affinity rolipram binding state (HARBS) of the phosphodiesterase-4 enzyme (PDE4) in rats
Psychopharmacology, 2006Co-Authors: Hanting Zhang, Ying Huang, Chengjun Deng, Allen T Hopper, Michael De Vivo, Gregory M Rose, Yu Zhao, James M. O’donnellAbstract:Rationale Phosphodiesterase-4 (PDE4) has two conformation states based on rolipram binding, the high-affinity rolipram binding state (HARBS) and the low-affinity rolipram binding state (LARBS); their functions remain to be fully explained. Objective Experiments were carried out to determine the roles of the HARBS and LARBS in the mediation of antidepressant-like effects on behavior. Materials and methods Two animal models sensitive to antidepressant drugs, the forced-swim test (FST), and the differential-reinforcement-of-low-rate (DRL) 72-s operant schedule, were used to examine the antidepressant-like effects of rolipram, CDP840, and piclamilast, PDE4 Inhibitors that interact differentially with the HARBS and LARBS, and MEM1018 and MEM1091, two novel PDE4 Inhibitors. Drug discrimination vs rolipram and rolipram competition binding assays also were carried out. Results In the FST, rolipram and piclamilast, both at 0.1 mg/kg, produced an antidepressant-like effect, i.e., reduced immobility and increased swimming, whereas, 1 mg/kg of CDP840 or 0.5 mg/kg of MEM1018 or MEM1091 was required to produce a similar effect. Consistent with this, only rolipram and piclamilast produced antidepressant-like effects in rats under the DRL schedule of reinforcement, as evidenced by decreased response rates and increased reinforcement rates. In addition, in rats trained to discriminate rolipram from its vehicle, only rolipram and piclamilast substituted. Finally, [^3H]rolipram and [^3H]piclamilast binding analysis revealed that CDP840 and the two novel PDE4 Inhibitors MEM1018 and MEM1091 exhibited a lower affinity for the HARBS than did rolipram. Conclusion These results suggest that the HARBS of PDE4 is the primary conformation important for antidepressant-like effects on behavior.
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Effects of the novel PDE4 Inhibitors MEM1018 and MEM1091 on memory in the radial-arm maze and inhibitory avoidance tests in rats
Psychopharmacology, 2005Co-Authors: Hanting Zhang, Ying Huang, Neesha U Suvarna, Chengjun Deng, Alicia M Crissman, Allen T Hopper, Michael De Vivo, Gregory M Rose, James M. O’donnellAbstract:Rationale Inhibition of cyclic AMP (cAMP)-specific phosphodiesterase (PDE4) enhances memory in rodents. MEM1018 and MEM1091 are newly developed PDE4 Inhibitors that had not been evaluated as yet for their effects on working and reference memory. Objective Experiments were carried out to determine whether these two drugs alter memory and if these effects are associated with changes in intracellular cAMP in the brain. Methods The effects of MEM1018 and MEM1091 on memory deficits induced by the N -methyl- d- aspartate (NMDA) receptor antagonist MK-801 were determined in the eight-arm radial maze and step-through inhibitory avoidance tasks in rats. Their effects on cAMP concentrations in primary cultures of rat cerebral cortical neurons and their potency for inhibiting recombinant PDE4 subtypes were examined. Results In the radial-arm maze, MEM1018 and MEM1091 (0.1–2.5 mg/kg, IP) enhanced working and reference memory impaired by MK-801 (0.1 mg/kg). In addition, both drugs antagonized the amnesic effect of MK-801 on passive avoidance behavior. Overall, the behavioral effects of MEM1018 and MEM1091 were similar to the prototypic PDE4 inhibitor rolipram (0.1 mg/kg). Consistent with this, and similar to the effects of rolipram, both MEM1018 (10–30 μM) and MEM1091 (10 μM) enhanced the ability of NMDA (30 μM) to increase cAMP concentrations in rat cerebral cortical neurons, in vitro. MEM1018 and MEM1091 showed greater relative selectivity for PDE4D than rolipram, although the general profiles of the three compounds were similar. Conclusions The novel PDE4 Inhibitors MEM1018 and MEM1091 enhance memory in a manner generally similar to rolipram. PDE4D may be the primary target for the PDE4 Inhibitors in the mediation of memory.