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Article ; Online: Allosteric Modalities for Membrane-Bound Receptors: Insights from Drug Hunting for Brain Diseases.

Coughlin, Quinn / Hopper, Allen T / Blanco, Maria-Jesus / Tirunagaru, Vijaya / Robichaud, Albert J / Doller, Dario

2019 Volume 62, Issue 13, Page(s) 5979–6002

Abstract: Medicinal chemists are accountable for embedding the appropriate drug target profile into the molecular architecture of a clinical candidate. An accurate characterization of the functional effects following binding of a drug to its biological target is a ...

Abstract	Medicinal chemists are accountable for embedding the appropriate drug target profile into the molecular architecture of a clinical candidate. An accurate characterization of the functional effects following binding of a drug to its biological target is a fundamental step in the discovery of new medicines, informing the translation of preclinical efficacy and safety observations into human trials. Membrane-bound proteins, particularly ion channels and G protein-coupled receptors (GPCRs), are biological targets prone to allosteric modulation. Investigations using allosteric drug candidates and chemical tools suggest that their functional effects may be tailored with a high degree of translational alignment, making them molecular tools to correct pathophysiological functional tone and enable personalized medicine when a causative target-to-disease link is known. We present select examples of functional molecular fine-tuning of allosterism and discuss consequences relevant to drug design.
MeSH term(s)	Allosteric Regulation ; Animals ; Brain Diseases/drug therapy ; Drug Design ; Humans ; Ion Channels/agonists ; Ion Channels/antagonists & inhibitors ; Molecular Structure ; Neurotransmitter Agents/chemistry ; Neurotransmitter Agents/pharmacology ; Receptors, G-Protein-Coupled/agonists ; Receptors, G-Protein-Coupled/antagonists & inhibitors ; Structure-Activity Relationship
Chemical Substances	Ion Channels ; Neurotransmitter Agents ; Receptors, G-Protein-Coupled
Language	English
Publishing date	2019-03-01
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	218133-2
ISSN	1520-4804 ; 0022-2623
ISSN (online)	1520-4804
ISSN	0022-2623
DOI	10.1021/acs.jmedchem.8b01651
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Article: Effects of CYP46A1 Inhibition on Long-Term-Depression in Hippocampal Slices

Popiolek, Michael / Izumi, Yukitoshi / Hopper, Allen T / Dai, Jing / Miller, Silke / Shu, Hong-Jin / Zorumski, Charles F / Mennerick, Steven

Frontiers in molecular neuroscience

2020 Volume 13, Page(s) 568641

Abstract: The manipulation of cholesterol and its metabolites has been hypothesized to be therapeutically beneficial for mood disorders, neurodegenerative disorders, and epilepsies. A major regulator of cholesterol clearance and turnover in the central nervous ... ...

Abstract	The manipulation of cholesterol and its metabolites has been hypothesized to be therapeutically beneficial for mood disorders, neurodegenerative disorders, and epilepsies. A major regulator of cholesterol clearance and turnover in the central nervous system is CYP46A1, a brain enriched enzyme responsible for metabolism of cholesterol into 24S-hydroxycholesterol. Inhibition of this enzyme may negatively modulate NMDARs as 24S-hydroxycholesterol was shown to enhance NMDAR function. In addition, alterations of local cholesterol or other changes mediated by CYP46A1 activity could have important influences on central nervous system function. Here we demonstrate that humans and mice display brain region specific and similar CYP46A1 and 24S-hydroxycholesterol distribution. Treatment with distinct classes of CYP46A1 inhibitors led to central 24S-hydroxycholesterol reduction
Language	English
Publishing date	2020-10-29
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2452967-9
ISSN	1662-5099
ISSN	1662-5099
DOI	10.3389/fnmol.2020.568641
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Article ; Online: Optimizing Pyrazolopyrimidine Inhibitors of Calcium Dependent Protein Kinase 1 for Treatment of Acute and Chronic Toxoplasmosis.

Janetka, James W / Hopper, Allen T / Yang, Ziping / Barks, Jennifer / Dhason, Mary Savari / Wang, Qiuling / Sibley, L David

Journal of medicinal chemistry

2020 Volume 63, Issue 11, Page(s) 6144–6163

Abstract: Calcium dependent protein kinase 1 (CDPK1) is an essential Ser/Thr kinase that controls invasion and egress by the protozoan ... ...

Abstract	Calcium dependent protein kinase 1 (CDPK1) is an essential Ser/Thr kinase that controls invasion and egress by the protozoan parasite
MeSH term(s)	Acute Disease ; Animals ; Binding Sites ; Cell Line ; Cell Proliferation/drug effects ; Chronic Disease ; Crystallography, X-Ray ; Cytochrome P-450 Enzyme System/metabolism ; Half-Life ; Humans ; Mice ; Molecular Conformation ; Molecular Dynamics Simulation ; Protein Kinase Inhibitors/chemistry ; Protein Kinase Inhibitors/pharmacokinetics ; Protein Kinase Inhibitors/pharmacology ; Protein Kinase Inhibitors/therapeutic use ; Protein Kinases/chemistry ; Protein Kinases/metabolism ; Protozoan Proteins/antagonists & inhibitors ; Protozoan Proteins/metabolism ; Pyrimidines/chemistry ; Pyrimidines/pharmacokinetics ; Pyrimidines/pharmacology ; Pyrimidines/therapeutic use ; Structure-Activity Relationship ; Toxoplasma/drug effects ; Toxoplasma/enzymology ; Toxoplasmosis/drug therapy
Chemical Substances	Protein Kinase Inhibitors ; Protozoan Proteins ; Pyrimidines ; Cytochrome P-450 Enzyme System (9035-51-2) ; Protein Kinases (EC 2.7.-)
Language	English
Publishing date	2020-06-01
Publishing country	United States
Document type	Journal Article
ZDB-ID	218133-2
ISSN	1520-4804 ; 0022-2623
ISSN (online)	1520-4804
ISSN	0022-2623
DOI	10.1021/acs.jmedchem.0c00419
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Article ; Online: P2X7 receptor-mediated release of microglial prostanoids and miRNAs correlates with reversal of neuropathic hypersensitivity in rats.

Staal, Roland / Khayrullina, Tanzilya / Christensen, Rie / Hestehave, Sara / Zhou, Hua / Cajina, Manuel / Nattini, Megan E / Gandhi, Adarsh / Fallon, Shaun M / Schmidt, Megan / Zorn, Stevin H / Brodbeck, Robbin M / Chandrasena, Gamini / Segerdahl, Märta / Breysse, Nathalie / Hopper, Allen T / Möller, Thomas / Munro, Gordon

European journal of pain (London, England)

2022 Volume 26, Issue 6, Page(s) 1304–1321

Abstract: Background: P2X7 receptor antagonists have potential for treating various central nervous system (CNS) diseases, including neuropathic pain, although none have been approved for clinical use. Reasons may include insufficient understanding of P2X7 ... ...

Abstract	Background: P2X7 receptor antagonists have potential for treating various central nervous system (CNS) diseases, including neuropathic pain, although none have been approved for clinical use. Reasons may include insufficient understanding of P2X7 receptor signalling in pain, and the lack of a corresponding preclinical mechanistic biomarker. Methods: Lu AF27139 is a highly selective and potent small molecule antagonist at rat, mouse and human forms of the P2X7 receptor, with excellent pharmacokinetic and CNS permeability properties. In the current experiments, we probed the utility of previously characterized and novel signalling cascades exposed to Lu AF27139 using cultured microglia combined with release assays. Subsequently, we assessed the biomarker potential of identified candidate molecules in the rat chronic constriction injury (CCI) model of neuropathic pain; study design limitations precluded their assessment in spared nerve injury (SNI) rats. Results: Lu AF27139 blocked several pain-relevant pathways downstream of P2X7 receptors in vitro. At brain and spinal cord receptor occupancy levels capable of functionally blocking P2X7 receptors, it diminished neuropathic hypersensitivity in SNI rats, and less potently in CCI rats. Although tissue levels of numerous molecules previously linked to neuropathic pain and P2X7 receptor function (e.g. IL-6, IL-1β, cathepsin-S, 2-AG) were unaffected by CCI, Lu AF27139-mediated regulation of spinal PGE2 and miRNA (e.g. rno-miR-93-5p) levels increased by CCI aligned with its ability to diminish neuropathic hypersensitivity. Conclusions: We have identified a pain-relevant P2X7 receptor-regulated mechanism in neuropathic rats, which could hold promise as a translatable biomarker and by association enhance the clinical progression of P2X7 receptor antagonists in neuropathic pain. Significance: Sub-optimal translation of preclinical molecules has hindered the clinical development of novel mechanism of action analgesics. We have undertaken a comprehensive in vitro analysis of migroglial signalling mechanisms recruited upon P2X7 receptor activation, a number of which were shown to be modulated by a selective P2X7 receptor antagonist in a well characterized animal model of neuropathic pain. Subject to further confirmation in other neuropathic models, this opens up the possibility to investigate their clinical utility as potential pain biomarkers in patients.
MeSH term(s)	Animals ; Hypersensitivity/metabolism ; MicroRNAs/metabolism ; Microglia/metabolism ; Neuralgia/metabolism ; Prostaglandins/metabolism ; Purinergic P2X Receptor Antagonists/pharmacology ; Rats ; Rats, Sprague-Dawley ; Receptors, Purinergic P2X7/metabolism ; Spinal Cord/metabolism
Chemical Substances	MicroRNAs ; Mirn93 microRNA, rat ; Prostaglandins ; Purinergic P2X Receptor Antagonists ; Receptors, Purinergic P2X7
Language	English
Publishing date	2022-04-22
Publishing country	England
Document type	Journal Article
ZDB-ID	1390424-3
ISSN	1532-2149 ; 1090-3801
ISSN (online)	1532-2149
ISSN	1090-3801
DOI	10.1002/ejp.1951
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Article ; Online: Discovery of Selective Toxoplasma gondii Dihydrofolate Reductase Inhibitors for the Treatment of Toxoplasmosis.

Hopper, Allen T / Brockman, Adam / Wise, Andy / Gould, Julie / Barks, Jennifer / Radke, Joshua B / Sibley, L David / Zou, Yongmao / Thomas, Stephen

Journal of medicinal chemistry

2019 Volume 62, Issue 3, Page(s) 1562–1576

Abstract: A safer treatment for toxoplasmosis would be achieved by improving the selectivity and potency of dihydrofolate reductase (DHFR) inhibitors, such as pyrimethamine (1), for Toxoplasma gondii DHFR ( TgDHFR) relative to human DHFR ( hDHFR). We previously ... ...

Abstract	A safer treatment for toxoplasmosis would be achieved by improving the selectivity and potency of dihydrofolate reductase (DHFR) inhibitors, such as pyrimethamine (1), for Toxoplasma gondii DHFR ( TgDHFR) relative to human DHFR ( hDHFR). We previously reported on the identification of meta-biphenyl analog 2, designed by in silico modeling of key differences in the binding pocket between TgDHFR and hDHFR. Compound 2 improves TgDHFR selectivity 6.6-fold and potency 16-fold relative to 1. Here, we report on the optimization and structure-activity relationships of this arylpiperazine series leading to the discovery of 5-(4-(3-(2-methoxypyrimidin-5-yl)phenyl)piperazin-1-yl)pyrimidine-2,4-diamine 3. Compound 3 has a TgDHFR IC
MeSH term(s)	Animals ; Antiparasitic Agents/chemical synthesis ; Antiparasitic Agents/chemistry ; Antiparasitic Agents/therapeutic use ; Dogs ; Female ; Folic Acid Antagonists/chemical synthesis ; Folic Acid Antagonists/chemistry ; Folic Acid Antagonists/therapeutic use ; Humans ; MCF-7 Cells ; Madin Darby Canine Kidney Cells ; Mice ; Molecular Structure ; Piperazines/chemical synthesis ; Piperazines/chemistry ; Piperazines/therapeutic use ; Pyrimidines/chemical synthesis ; Pyrimidines/chemistry ; Pyrimidines/therapeutic use ; Structure-Activity Relationship ; Tetrahydrofolate Dehydrogenase/metabolism ; Toxoplasma/enzymology ; Toxoplasmosis/drug therapy
Chemical Substances	Antiparasitic Agents ; Folic Acid Antagonists ; Piperazines ; Pyrimidines ; Tetrahydrofolate Dehydrogenase (EC 1.5.1.3)
Language	English
Publishing date	2019-01-24
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	218133-2
ISSN	1520-4804 ; 0022-2623
ISSN (online)	1520-4804
ISSN	0022-2623
DOI	10.1021/acs.jmedchem.8b01754
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Article ; Online: Synthesis and Characterization of the Novel Rodent-Active and CNS-Penetrant P2X7 Receptor Antagonist Lu AF27139.

Hopper, Allen T / Juhl, Martin / Hornberg, Jorrit / Badolo, Lassina / Kilburn, John Paul / Thougaard, Annemette / Smagin, Gennady / Song, Dekun / Calice, Londye / Menon, Veena / Dale, Elena / Zhang, Hong / Cajina, Manuel / Nattini, Megan E / Gandhi, Adarsh / Grenon, Michel / Jones, Ken / Khayrullina, Tanzilya / Chandrasena, Gamini /

Thomsen, Christian / Zorn, Stevin H / Brodbeck, Robb / Poda, Suresh Babu / Staal, Roland / Möller, Thomas

Journal of medicinal chemistry

2021 Volume 64, Issue 8, Page(s) 4891–4902

Abstract: There remains an insufficient number of P2X7 receptor antagonists with adequate rodent potency, CNS permeability, and pharmacokinetic properties from which to evaluate CNS disease hypotheses preclinically. Herein, we describe the molecular pharmacology, ... ...

Abstract	There remains an insufficient number of P2X7 receptor antagonists with adequate rodent potency, CNS permeability, and pharmacokinetic properties from which to evaluate CNS disease hypotheses preclinically. Herein, we describe the molecular pharmacology, safety, pharmacokinetics, and functional CNS target engagement of Lu AF27139, a novel rodent-active and CNS-penetrant P2X7 receptor antagonist. Lu AF27139 is highly selective and potent against rat, mouse, and human forms of the receptors. The rat pharmacokinetic profile is favorable with high oral bioavailability, modest clearance (0.79 L/(h kg)), and good CNS permeability.
MeSH term(s)	Adenosine Triphosphate/analogs & derivatives ; Adenosine Triphosphate/pharmacology ; Animals ; Cell Line ; Central Nervous System/drug effects ; Central Nervous System/metabolism ; Dogs ; Female ; Half-Life ; Humans ; Interleukin-1beta/metabolism ; Lipopolysaccharides/pharmacology ; Male ; Mice ; Mice, Inbred C57BL ; Microglia/cytology ; Microglia/drug effects ; Microglia/metabolism ; Microsomes, Liver/metabolism ; Monocytes/cytology ; Monocytes/drug effects ; Monocytes/metabolism ; Purinergic P2X Receptor Antagonists/chemical synthesis ; Purinergic P2X Receptor Antagonists/metabolism ; Purinergic P2X Receptor Antagonists/pharmacology ; Rats ; Rats, Sprague-Dawley ; Receptors, Purinergic P2X7/chemistry ; Receptors, Purinergic P2X7/metabolism
Chemical Substances	Interleukin-1beta ; Lipopolysaccharides ; Purinergic P2X Receptor Antagonists ; Receptors, Purinergic P2X7 ; 3'-O-(4-benzoyl)benzoyladenosine 5'-triphosphate (4P5DXU1F8Q) ; Adenosine Triphosphate (8L70Q75FXE)
Language	English
Publishing date	2021-04-06
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	218133-2
ISSN	1520-4804 ; 0022-2623
ISSN (online)	1520-4804
ISSN	0022-2623
DOI	10.1021/acs.jmedchem.0c02249
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Article ; Online: Fused thiazolyl alkynes as potent mGlu5 receptor positive allosteric modulators.

Packiarajan, Mathivanan / Grenon, Michel / Zorn, Samuel / Hopper, Allen T / White, Andrew D / Chandrasena, Gamini / Pu, Xiaosui / Brodbeck, Robbin M / Robichaud, Albert J

Bioorganic & medicinal chemistry letters

2013 Volume 23, Issue 14, Page(s) 4037–4043

Abstract: A new series of potent fused thiazole mGlu5 receptor positive allosteric modulators (PAMs) (10, 11 and 27-31) are disclosed and details of the SAR and optimization are described. Optimization of alkynyl thiazole 9 (Lu AF11205) led to the identification ... ...

Abstract	A new series of potent fused thiazole mGlu5 receptor positive allosteric modulators (PAMs) (10, 11 and 27-31) are disclosed and details of the SAR and optimization are described. Optimization of alkynyl thiazole 9 (Lu AF11205) led to the identification of potent fused thiazole analogs 10b, 27a, 28j and 31d. In general, substituted cycloalkyl, aryl and heteroaryl carboxamides, and carbamate analogs are mGlu5PAMs, whereas smaller alkyl carboxamide, sulfonamide and sulfamide analogs tend to be mGlu5 negative allosteric modulators (NAMs).
MeSH term(s)	Alkynes/chemistry ; Allosteric Regulation ; Amides/chemical synthesis ; Amides/chemistry ; Amides/metabolism ; Carbamates/chemical synthesis ; Carbamates/chemistry ; Carbamates/metabolism ; Humans ; Protein Binding ; Receptor, Metabotropic Glutamate 5/chemistry ; Receptor, Metabotropic Glutamate 5/metabolism ; Structure-Activity Relationship ; Thiazoles/chemical synthesis ; Thiazoles/chemistry ; Thiazoles/metabolism
Chemical Substances	Alkynes ; Amides ; Carbamates ; Receptor, Metabotropic Glutamate 5 ; Thiazoles
Language	English
Publishing date	2013-07-15
Publishing country	England
Document type	Journal Article
ZDB-ID	1063195-1
ISSN	1464-3405 ; 0960-894X
ISSN (online)	1464-3405
ISSN	0960-894X
DOI	10.1016/j.bmcl.2013.05.070
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Article: Fused thiazolyl alkynes as potent mGlu₅ receptor positive allosteric modulators

Packiarajan, Mathivanan / Grenon, Michel / Zorn, Samuel / Hopper, Allen T / White, Andrew D / Chandrasena, Gamini / Pu, Xiaosui / Brodbeck, Robbin M / Robichaud, Albert J

Bioorganic & medicinal chemistry letters. 2013 July 15, v. 23, no. 14

2013

Abstract: A new series of potent fused thiazole mGlu₅ receptor positive allosteric modulators (PAMs) (10, 11 and 27–31) are disclosed and details of the SAR and optimization are described. Optimization of alkynyl thiazole 9 (Lu AF11205) led to the identification ... ...

Abstract	A new series of potent fused thiazole mGlu₅ receptor positive allosteric modulators (PAMs) (10, 11 and 27–31) are disclosed and details of the SAR and optimization are described. Optimization of alkynyl thiazole 9 (Lu AF11205) led to the identification of potent fused thiazole analogs 10b, 27a, 28j and 31d. In general, substituted cycloalkyl, aryl and heteroaryl carboxamides, and carbamate analogs are mGlu₅PAMs, whereas smaller alkyl carboxamide, sulfonamide and sulfamide analogs tend to be mGlu₅ negative allosteric modulators (NAMs).
Keywords	G-protein coupled receptors ; alkynes ; regulatory proteins ; structure-activity relationships
Language	English
Dates of publication	2013-0715
Size	p. 4037-4043.
Publishing place	Elsevier Ltd
Document type	Article
ZDB-ID	1063195-1
ISSN	1464-3405 ; 0960-894X
ISSN (online)	1464-3405
ISSN	0960-894X
DOI	10.1016/j.bmcl.2013.05.070
Database	NAL-Catalogue (AGRICOLA)

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Article: Antidepressant-like effects of PDE4 inhibitors mediated by the high-affinity rolipram binding state (HARBS) of the phosphodiesterase-4 enzyme (PDE4) in rats.

Zhang, Han-Ting / Zhao, Yu / Huang, Ying / Deng, Chengjun / Hopper, Allen T / De Vivo, Michael / Rose, Gregory M / O'Donnell, James M

Psychopharmacology

2006 Volume 186, Issue 2, Page(s) 209–217

Abstract: 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! ...

Abstract	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, [(3)H]rolipram and [(3)H]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.
MeSH term(s)	3',5'-Cyclic-AMP Phosphodiesterases/antagonists & inhibitors ; Animals ; Antidepressive Agents/pharmacology ; Behavior, Animal/drug effects ; Binding, Competitive ; Cyclic Nucleotide Phosphodiesterases, Type 4 ; Male ; Phosphodiesterase Inhibitors/pharmacology ; Radioligand Assay ; Rats ; Rats, Sprague-Dawley ; Rolipram/pharmacology
Chemical Substances	Antidepressive Agents ; Phosphodiesterase Inhibitors ; 3',5'-Cyclic-AMP Phosphodiesterases (EC 3.1.4.17) ; Cyclic Nucleotide Phosphodiesterases, Type 4 (EC 3.1.4.17) ; Rolipram (K676NL63N7)
Language	English
Publishing date	2006-06
Publishing country	Germany
Document type	Comparative Study ; Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	130601-7
ISSN	1432-2072 ; 0033-3158
ISSN (online)	1432-2072
ISSN	0033-3158
DOI	10.1007/s00213-006-0369-4
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Article: Effects of the novel PDE4 inhibitors MEM1018 and MEM1091 on memory in the radial-arm maze and inhibitory avoidance tests in rats.

Zhang, Han-Ting / Huang, Ying / Suvarna, Neesha U / Deng, Chengjun / Crissman, Alicia M / Hopper, Allen T / De Vivo, Michael / Rose, Gregory M / O'Donnell, James M

Psychopharmacology

2005 Volume 179, Issue 3, Page(s) 613–619

Abstract: 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.: ... ...

Abstract	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 microM) and MEM1091 (10 microM) enhanced the ability of NMDA (30 microM) 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.
MeSH term(s)	3',5'-Cyclic-AMP Phosphodiesterases/antagonists & inhibitors ; 3',5'-Cyclic-AMP Phosphodiesterases/physiology ; Animals ; Avoidance Learning/drug effects ; Avoidance Learning/physiology ; Cells, Cultured ; Cerebral Cortex/drug effects ; Cerebral Cortex/enzymology ; Cyclic Nucleotide Phosphodiesterases, Type 4 ; Dose-Response Relationship, Drug ; Male ; Maze Learning/drug effects ; Maze Learning/physiology ; Memory/drug effects ; Memory/physiology ; Phosphodiesterase Inhibitors/pharmacology ; Rats ; Rats, Sprague-Dawley
Chemical Substances	Phosphodiesterase Inhibitors ; 3',5'-Cyclic-AMP Phosphodiesterases (EC 3.1.4.17) ; Cyclic Nucleotide Phosphodiesterases, Type 4 (EC 3.1.4.17)
Language	English
Publishing date	2005-05
Publishing country	Germany
Document type	Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	130601-7
ISSN	1432-2072 ; 0033-3158
ISSN (online)	1432-2072
ISSN	0033-3158
DOI	10.1007/s00213-004-2085-2
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In stock of ZB MED Cologne/Königswinter

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In stock of ZB MED Cologne/Königswinter

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