Davis RE

General

Full name : Davis Robert E

First name : Robert E

Mail : Parke-Davis Pharmaceutical Research Division, 2800 Plymouth Road, Ann Arbor. Mi 48105-2430

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Country : USA

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Phone : (l) 3139967637

Fax : (l) 313 996 7178

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References (19)

Title : Genome and secretome analysis of the hemibiotrophic fungal pathogen, Moniliophthora roreri, which causes frosty pod rot disease of cacao: mechanisms of the biotrophic and necrotrophic phases - Meinhardt_2014_BMC.Genomics_15_164
Author(s) : Meinhardt LW , Costa GG , Thomazella DP , Teixeira PJ , Carazzolle MF , Schuster SC , Carlson JE , Guiltinan MJ , Mieczkowski P , Farmer A , Ramaraj T , Crozier J , Davis RE , Shao J , Melnick RL , Pereira GA , Bailey BA
Ref : BMC Genomics , 15 :164 , 2014
Abstract : BACKGROUND: The basidiomycete Moniliophthora roreri is the causal agent of Frosty pod rot (FPR) disease of cacao (Theobroma cacao), the source of chocolate, and FPR is one of the most destructive diseases of this important perennial crop in the Americas. This hemibiotroph infects only cacao pods and has an extended biotrophic phase lasting up to sixty days, culminating in plant necrosis and sporulation of the fungus without the formation of a basidiocarp.
RESULTS: We sequenced and assembled 52.3 Mb into 3,298 contigs that represent the M. roreri genome. Of the 17,920 predicted open reading frames (OFRs), 13,760 were validated by RNA-Seq. Using read count data from RNA sequencing of cacao pods at 30 and 60 days post infection, differential gene expression was estimated for the biotrophic and necrotrophic phases of this plant-pathogen interaction. The sequencing data were used to develop a genome based secretome for the infected pods. Of the 1,535 genes encoding putative secreted proteins, 1,355 were expressed in the biotrophic and necrotrophic phases. Analysis of the data revealed secretome gene expression that correlated with infection and intercellular growth in the biotrophic phase and invasive growth and plant cellular death in the necrotrophic phase.
CONCLUSIONS: Genome sequencing and RNA-Seq was used to determine and validate the Moniliophthora roreri genome and secretome. High sequence identity between Moniliophthora roreri genes and Moniliophthora perniciosa genes supports the taxonomic relationship with Moniliophthora perniciosa and the relatedness of this fungus to other basidiomycetes. Analysis of RNA-Seq data from infected plant tissues revealed differentially expressed genes in the biotrophic and necrotrophic phases. The secreted protein genes that were upregulated in the biotrophic phase are primarily associated with breakdown of the intercellular matrix and modification of the fungal mycelia, possibly to mask the fungus from plant defenses. Based on the transcriptome data, the upregulated secreted proteins in the necrotrophic phase are hypothesized to be actively attacking the plant cell walls and plant cellular components resulting in necrosis. These genes are being used to develop a new understanding of how this disease interaction progresses and to identify potential targets to reduce the impact of this devastating disease.
ESTHER : Meinhardt_2014_BMC.Genomics_15_164
PubMedSearch : Meinhardt_2014_BMC.Genomics_15_164
PubMedID: 24571091
Gene_locus related to this paper: monro-v2wn76 , monro-v2xuz8 , monro-v2xl67 , monro-v2xnp4 , monro-v2wv67 , monro-v2wja9

Title : Silencing of germline-expressed genes by DNA elimination in somatic cells - Wang_2012_Dev.Cell_23_1072
Author(s) : Wang J , Mitreva M , Berriman M , Thorne A , Magrini V , Koutsovoulos G , Kumar S , Blaxter ML , Davis RE
Ref : Dev Cell , 23 :1072 , 2012
Abstract : Chromatin diminution is the programmed elimination of specific DNA sequences during development. It occurs in diverse species, but the function(s) of diminution and the specificity of sequence loss remain largely unknown. Diminution in the nematode Ascaris suum occurs during early embryonic cleavages and leads to the loss of germline genome sequences and the formation of a distinct genome in somatic cells. We found that approximately 43 Mb ( approximately 13%) of genome sequence is eliminated in A. suum somatic cells, including approximately 12.7 Mb of unique sequence. The eliminated sequences and location of the DNA breaks are the same in all somatic lineages from a single individual and between different individuals. At least 685 genes are eliminated. These genes are preferentially expressed in the germline and during early embryogenesis. We propose that diminution is a mechanism of germline gene regulation that specifically removes a large number of genes involved in gametogenesis and early embryogenesis.
ESTHER : Wang_2012_Dev.Cell_23_1072
PubMedSearch : Wang_2012_Dev.Cell_23_1072
PubMedID: 23123092
Gene_locus related to this paper: ascsu-f1kr69 , ascsu-f1kxs8 , ascsu-f1ky57 , ascsu-f1kze8 , ascsu-f1kzv8 , ascsu-f1kzx8 , ascsu-f1l0a5 , ascsu-f1l0j3 , ascsu-f1l0s5 , ascsu-f1l1m9 , ascsu-f1l2e5 , ascsu-f1l3k2 , ascsu-f1l7s2 , ascsu-f1l145 , ascsu-u1mei8 , ascsu-u1ns34 , ascsu-u1nb30 , ascsu-f1kzg5 , ascsu-u1ntf1 , ascsu-u1nx87 , ascsu-f1l5f0 , ascsu-f1l6n2

Title : Deep small RNA sequencing from the nematode Ascaris reveals conservation, functional diversification, and novel developmental profiles - Wang_2011_Genome.Res_21_1462
Author(s) : Wang J , Czech B , Crunk A , Wallace A , Mitreva M , Hannon GJ , Davis RE
Ref : Genome Res , 21 :1462 , 2011
Abstract : Eukaryotic cells express several classes of small RNAs that regulate gene expression and ensure genome maintenance. Endogenous siRNAs (endo-siRNAs) and Piwi-interacting RNAs (piRNAs) mainly control gene and transposon expression in the germline, while microRNAs (miRNAs) generally function in post-transcriptional gene silencing in both somatic and germline cells. To provide an evolutionary and developmental perspective on small RNA pathways in nematodes, we identified and characterized known and novel small RNA classes through gametogenesis and embryo development in the parasitic nematode Ascaris suum and compared them with known small RNAs of Caenorhabditis elegans. piRNAs, Piwi-clade Argonautes, and other proteins associated with the piRNA pathway have been lost in Ascaris. miRNAs are synthesized immediately after fertilization in utero, before pronuclear fusion, and before the first cleavage of the zygote. This is the earliest expression of small RNAs ever described at a developmental stage long thought to be transcriptionally quiescent. A comparison of the two classes of Ascaris endo-siRNAs, 22G-RNAs and 26G-RNAs, to those in C. elegans, suggests great diversification and plasticity in the use of small RNA pathways during spermatogenesis in different nematodes. Our data reveal conserved characteristics of nematode small RNAs as well as features unique to Ascaris that illustrate significant flexibility in the use of small RNAs pathways, some of which are likely an adaptation to Ascaris' life cycle and parasitism. The transcriptome assembly has been submitted to NCBI Transcriptome Shotgun Assembly Sequence Database(http:\/\/www.ncbi.nlm.nih.gov/genbank/TSA.html) under accession numbers JI163767-JI182837 and JI210738-JI257410.
ESTHER : Wang_2011_Genome.Res_21_1462
PubMedSearch : Wang_2011_Genome.Res_21_1462
PubMedID: 21685128
Gene_locus related to this paper: ascsu-f1kpy0.2 , ascsu-f1kpy0.3 , ascsu-f1kpy0.4 , ascsu-f1kr69 , ascsu-f1ktc3 , ascsu-f1ktc5 , ascsu-f1ktw1.1 , ascsu-f1ktw1.2 , ascsu-f1ktx4 , ascsu-f1kwb2 , ascsu-f1kwb5 , ascsu-f1kwf0 , ascsu-f1kxs8 , ascsu-f1ky57 , ascsu-f1kz22 , ascsu-f1kze8 , ascsu-f1kzv8 , ascsu-f1kzx8 , ascsu-f1l0a5 , ascsu-f1l0j3 , ascsu-f1l0s4 , ascsu-f1l0s5 , ascsu-f1l1k4 , ascsu-f1l1m9 , ascsu-f1l1p8 , ascsu-f1l2e5 , ascsu-f1l2m0 , ascsu-f1l3k2 , ascsu-f1l5n5 , ascsu-f1l6s4 , ascsu-f1l7s2 , ascsu-f1l108 , ascsu-f1l145 , ascsu-f1la00 , ascsu-f1lav9 , ascsu-u1mei8 , ascsu-u1ns34 , ascsu-u1nb30 , ascsu-f1kzg5 , ascsu-f1l726 , ascsu-u1ntf1 , ascsu-u1nx87 , ascsu-f1l5f0 , ascsu-f1l6n2

Title : AC-260584, an orally bioavailable M(1) muscarinic receptor allosteric agonist, improves cognitive performance in an animal model - Bradley_2010_Neuropharmacol_58_365
Author(s) : Bradley SR , Lameh J , Ohrmund L , Son T , Bajpai A , Nguyen D , Friberg M , Burstein ES , Spalding TA , Ott TR , Schiffer HH , Tabatabaei A , McFarland K , Davis RE , Bonhaus DW
Ref : Neuropharmacology , 58 :365 , 2010
Abstract : The recent discovery of allosteric potentiators and agonists of the muscarinic M(1) receptor represents a significant advance in the muscarinic receptor pharmacology. In the current study we describe the receptor pharmacology and pro-cognitive action of the allosteric agonist AC-260584. Using in vitro cell-based assays with cell proliferation, phosphatidylinositol hydrolysis or calcium mobilization as endpoints, AC-260584 was found to be a potent (pEC(50) 7.6-7.7) and efficacious (90-98% of carbachol) muscarinic M(1) receptor agonist. Furthermore, as compared to orthosteric binding agonists, AC-260584 showed functional selectivity for the M(1) receptor over the M(2), M(3), M(4) and M(5) muscarinic receptor subtypes. Using GTPgammaS binding assays, its selectivity was found to be similar in native tissues expressing mAChRs to its profile in recombinant systems. In rodents, AC-260584 activated extracellular signal-regulated kinase 1 and 2 (ERK1/2) phosphorylation in the hippocampus, prefrontal cortex and perirhinal cortex. The ERK1/2 activation was dependent upon muscarinic M(1) receptor activation since it was not observed in M(1) knockout mice. AC-260584 also improved the cognitive performance of mice in the novel object recognition assay and its action is blocked by the muscarinic receptor antagonist pirenzepine. Taken together these results indicate for the first time that a M(1) receptor agonist selective over the other mAChR subtypes can have a symptomatically pro-cognitive action. In addition, AC-260584 was found to be orally bioavailable in rodents. Therefore, AC-260584 may serve as a lead compound in the development of M(1) selective drugs for the treatment of cognitive impairment associated with schizophrenia and Alzheimer's disease.
ESTHER : Bradley_2010_Neuropharmacol_58_365
PubMedSearch : Bradley_2010_Neuropharmacol_58_365
PubMedID: 19835892

Title : Sequence-variable mosaics: composites of recurrent transposition characterizing the genomes of phylogenetically diverse phytoplasmas - Jomantiene_2007_DNA.Cell.Biol_26_557
Author(s) : Jomantiene R , Zhao Y , Davis RE
Ref : DNA & Cell Biology , 26 :557 , 2007
Abstract : Phytoplasmas are cell wall-less prokaryotes characterized by small, AT-rich genomes that encode capabilities for obligate, transkingdom parasitism and pathogenicity in plants and insect vectors. Inability to isolate and characterize phytoplasmas in pure culture has led to adoption of the 'Candidatus species' convention to refer to distinct phytoplasma lineages. In this study, we provide evidence that multiple, sequence-variable mosaics (SVMs) of clustered genes and repetitive extragenic palindromes are characteristic features of phytoplasma genome architecture in phylogenetically diverse species. The findings suggest that the origin of SVMs was an ancient event in evolution of the phytoplasma clade, while current forms of SVMs are results of dramatic and more recent events. Sequence diversity of hypervariable regions indicated rapid evolution possibly involving capture of mobile elements recurrently targeted to SVMs. Multiple events of targeted mobile element attack, recombination, and rearrangement conceivably account for the composite structure of SVMs. Proteins encoded by the highly variable region included a lysophospholipase and other putatively secreted and/or transmembrane, cell surface-interacting proteins potentially significant in phytoplasma-host interactions.
ESTHER : Jomantiene_2007_DNA.Cell.Biol_26_557
PubMedSearch : Jomantiene_2007_DNA.Cell.Biol_26_557
PubMedID: 17688407
Gene_locus related to this paper: 9molu-a8qwc7

Title : Structural requirements of transmembrane domain 3 for activation by the M1 muscarinic receptor agonists AC-42, AC-260584, clozapine, and N-desmethylclozapine: evidence for three distinct modes of receptor activation - Spalding_2006_Mol.Pharmacol_70_1974
Author(s) : Spalding TA , Ma JN , Ott TR , Friberg M , Bajpai A , Bradley SR , Davis RE , Brann MR , Burstein ES
Ref : Molecular Pharmacology , 70 :1974 , 2006
Abstract : Transmembrane domain 3 (TM3) plays a crucial role mediating muscarinic acetylcholine receptor activation by acetylcholine, carbachol, and other muscarinic agonists. We compared the effects of point mutations throughout TM3 on the interactions of carbachol, 4-n-butyl-1-[4-(2-methylphenyl)-4-oxo-1-butyl] piperidine hydrogen chloride (AC-42), a potent structural analog of AC-42 called 4-[3-(4-butylpiperidin-1-yl)-propyl]-7-fluoro-4H-benzo[1,4]oxazin-3-one (AC-260584), N-desmethylclozapine, and clozapine with the M(1) muscarinic receptor. The binding and activation profiles of these ligands fell into three distinct patterns; one exemplified by orthosteric compounds like carbachol, another by structural analogs of AC-42, and a third by structural analogs of N-desmethylclozapine. All mutations tested severely reduced carbachol binding and activation of M(1). In contrast, the agonist actions of AC-42 and AC-260584 were greatly potentiated by the W101A mutation, slightly reduced by Y106A, and slightly increased by S109A. Clozapine and N-desmethylclozapine displayed substantially increased maximum responses at the Y106A and W101A mutants, slightly lower activity at S109A, but no substantial changes in potency. At L102A and N110A, agonist responses to AC-42, AC-260584, clozapine, and N-desmethylclozapine were all substantially reduced, but usually less than carbachol. D105A showed no functional responses to all ligands. Displacement and dissociation rate experiments demonstrated clear allosteric properties of AC-42 and AC-260584 but not for N-desmethylclozapine and clozapine, indicating that they may contact different residues than carbachol to activate M(1) but occupy substantially overlapping spaces, in contrast to AC-42 and AC-260584, which occupy separable spaces. These results show that M(1) receptors can be activated in at least three distinct ways and that there is no requirement for potent muscarinic agonists to mimic acetylcholine interactions with TM3.
ESTHER : Spalding_2006_Mol.Pharmacol_70_1974
PubMedSearch : Spalding_2006_Mol.Pharmacol_70_1974
PubMedID: 16959945

Title : The role of M1 muscarinic receptor agonism of N-desmethylclozapine in the unique clinical effects of clozapine - Weiner_2004_Psychopharmacology.(Berl)_177_207
Author(s) : Weiner DM , Meltzer HY , Veinbergs I , Donohue EM , Spalding TA , Smith TT , Mohell N , Harvey SC , Lameh J , Nash N , Vanover KE , Olsson R , Jayathilake K , Lee M , Levey AI , Hacksell U , Burstein ES , Davis RE , Brann MR
Ref : Psychopharmacology (Berl) , 177 :207 , 2004
Abstract : RATIONALE: Clozapine is a unique antipsychotic, with efficacy against positive symptoms in treatment-resistant schizophrenic patients, and the ability to improve cognition and treat the negative symptoms characteristic of this disease. Despite its unique clinical actions, no specific molecular mechanism responsible for these actions has yet been described. OBJECTIVES AND
METHODS: To comprehensively profile a large library of neuropsychiatric drugs, including most antipsychotics, at human monoamine receptors using R-SAT, an in vitro functional assay.
RESULTS: Profiling revealed that N-desmethylclozapine (NDMC), the principal metabolite of clozapine, but not clozapine itself, is a potent and efficacious muscarinic receptor agonist, a molecular property not shared by any other antipsychotic. To further explore the role of NDMC muscarinic receptor agonist properties in mediating the physiological actions of clozapine, systemically administered NDMC was found to stimulate the phosphorylation of mitogen-activated protein kinase (MAP kinase) in mouse CA1 hippocampal neurons, an effect that was blocked by scopolamine, confirming central M1 muscarinic receptor agonist activity in vivo. Lastly, an analysis of clozapine and NDMC serum levels in schizophrenic patients indicated that high NDMC/clozapine ratios better predicted improvement in cognitive functioning and quality of life than the levels of either compound alone.
CONCLUSIONS: The muscarinic receptor agonist activities of NDMC are unique among antipsychotics, and provide a possible molecular basis for the superior clinical effects of clozapine pharmacotherapy.
ESTHER : Weiner_2004_Psychopharmacology.(Berl)_177_207
PubMedSearch : Weiner_2004_Psychopharmacology.(Berl)_177_207
PubMedID: 15258717

Title : CI-1017, a functionally M1-selective muscarinic agonist: design, synthesis, and preclinical pharmacology - Tecle_2000_Pharm.Acta.Helv_74_141
Author(s) : Tecle H , Schwarz RD , Barrett SD , Callahan MJ , Caprathe BW , Davis RE , Doyle P , Emmerling M , Lauffer DJ , Mirzadegan T , Moreland DW , Lipiniski W , Nelson C , Raby C , Spencer C , Spiegel K , Thomas AJ , Jaen JC
Ref : Pharm Acta Helv , 74 :141 , 2000
Abstract : The five muscarinic receptor subtypes (M1-M5) are characterized by seven helices that define a transmembrane cavity which serves as the binding pocket for agonists and antagonists. The five cavities appear to be topographically different enough to permit subtype selectivity among antagonists but not among classical agonists which tend to be smaller in size than antagonists. It was reasoned that synthesis of muscarinic agonists longer/larger than their classical counterparts might result in subtype selectivity. M1 subtype selectivity was found in a class of 1-azabicyclo[2.2.1]heptan-3-one, O-(3-aryl-2-propynyl) oximes. One of these, CI-1017, improved spatial memory of hippocampally deficient mice and nbM-lesioned rats at doses of 1.0-3.2 and 0.1-0.3 mg/kg, respectively, while producing parasympathetic side effects only at very high doses (100-178 mg/kg). Additionally, CI-1017 inhibited production of amyloidogenic A beta and increased secretion of soluble APP. Thus, CI-1017, besides treating AD symptomatically, may also retard its progression. CI-1017 has recently completed phase I clinical trials.
ESTHER : Tecle_2000_Pharm.Acta.Helv_74_141
PubMedSearch : Tecle_2000_Pharm.Acta.Helv_74_141
PubMedID: 10812951

Title : Design and synthesis of m1-selective muscarinic agonists: (R)-(-)-(Z)-1-Azabicyclo[2.2.1]heptan-3-one, O-(3-(3'-methoxyphenyl)-2-propynyl)oxime maleate (CI-1017), a functionally m1-selective muscarinic agonist - Tecle_1998_J.Med.Chem_41_2524
Author(s) : Tecle H , Barrett SD , Lauffer DJ , Augelli-Szafran C , Brann MR , Callahan MJ , Caprathe BW , Davis RE , Doyle PD , Eubanks D , Lipiniski W , Mirzadegan T , Moos WH , Moreland DW , Nelson CB , Pavia MR , Raby C , Schwarz RD , Spencer CJ , Thomas AJ , Jaen JC
Ref : Journal of Medicinal Chemistry , 41 :2524 , 1998
Abstract : The synthesis and SAR of a series of (Z)-(+/-)-1-azabicyclo[2.2. 1]heptan-3-one, O-(3-aryl-2-propynyl)oximes are described. The biochemistry and pharmacology of 24Z (PD 142505) and its enantiomers are highlighted. 24Z is functionally an m1-selective muscarinic agonist. Efficacy and m1 selectivity reside in the R enantiomer, (R)-24Z (CI-1017).
ESTHER : Tecle_1998_J.Med.Chem_41_2524
PubMedSearch : Tecle_1998_J.Med.Chem_41_2524
PubMedID: 9651157

Title : Poster: Aryleneyne 1-azabicyclo[2.2.1]heptan-3-one oximes: Potent muscarinic agonists -
Author(s) : Tecle H , Lauffer DJ , Davis RE , Mirzadegan T , Moreland DW , Schwarz RD , Thomas AJ , Raby C , Jaen JC
Ref : Life Sciences , 56(11-12) :1003 , 1995
PubMedID:

Title : Cholinergic therapies for Alzheimer's disease. Palliative or disease altering? - Davis_1995_Arzneimittelforschung_45_425
Author(s) : Davis RE , Doyle PD , Carroll RT , Emmerling MR , Jaen J
Ref : Arzneimittelforschung , 45 :425 , 1995
Abstract : Loss of cholinergic function in the neocortex and hippocampus arising from death or atrophy of basal forebrain cholinergic neurons is a consistent feature of the Alzheimer brain at autopsy or biopsy. Replacement of lost cholinergic function, therefore, may be of therapeutic benefit to the Alzheimer's (AD) patients. This can be accomplished by enhancing endogenous levels of acetylcholine (ACh) through inhibition of its degradation by acetylcholinesterase on by directly mimicking its actions at postsynaptic muscarinic receptors. Initial efforts focused on inhibition of cholinesterase activity with tacrine (1,2,3,4-tetrahydroaminoacridine monochloride, CAS 1684-40-8, THA, Cognex). Tacrine is a mixed, reversible inhibitor of cholinesterase activity that binds near but not to the catalytically active serine in the active site of the enzyme. Through this action tacrine indirectly elevates ACh levels in the brains of animals and improves cognitive performance in rodents and monkeys. More importantly, tacrine has been shown to significantly improve several measures of cognitive performance in probable AD patients in well-controlled clinical trials, although not all patients respond to this agent. CI-979 ((E)-1,2,5,6-tetrahydro-1-methyl-3-pyridine-carboxyaldehyde-O-meth yl oxime, CAS 139886-04-7) is a non-subtype selective, partial muscarinic agonist that enhances cognitive performance and increases central cholinergic activity in rodents at doses below those required to increase peripheral cholinergic tone. In normal healthy volunteers, CI-979 is well tolerated at single and multiple doses (q 6 h) up to 1.0 mg. In normal healthy volunteers, CI-979 is well tolerated at single and multiple doses (q 6 h) up to 1.0 mg. Expected signs of mild to moderate peripheral cholinergic stimulation were noted at 0.5 to 1.0 mg doses (q 6 h).(ABSTRACT TRUNCATED AT 250 WORDS)
ESTHER : Davis_1995_Arzneimittelforschung_45_425
PubMedSearch : Davis_1995_Arzneimittelforschung_45_425
PubMedID: 7763338

Title : PD 142676 (CI 1002), a novel anticholinesterase and muscarinic antagonist - Emmerling_1994_Mol.Neurobiol_9_93
Author(s) : Emmerling MR , Gregor VE , Schwarz RD , Scholten JD , Callahan MJ , Lee C , Moore CJ , Raby C , Lipinski WJ , Davis RE
Ref : Molecular Neurobiology , 9 :93 , 1994
Abstract : Inhibition of brain acetylcholinesterase (AChE) can provide relief from the cognitive loss associated with Alzheimer's disease (AD). However, unwanted peripheral side effects often limit the usefulness of the available anticholinesterases. Recently, we identified a dihydroquinazoline compound, PD 142676 (CI 1002) that is a potent anticholinesterase and a functional muscarinic antagonist at higher concentrations. Peripherally, PD 142676, unlike other anticholinesterases, inhibits gastrointestinal motility in rats, an effect consistent with its muscarinic antagonist properties. Centrally, the compound acts as a cholinomimetic. In rats, PD 142676 decreases core body temperature. It also increases neocortical arousal, as measured by quantitative electroencephalography, and cortical acetylcholine levels, measured by in vivo microdialysis. The compound improves the performance of C57/B10j mice in a water maze task and of aged rhesus monkeys in a delayed match-to-sample task involving short-term memory. The combined effect of AChE inhibition and muscarinic antagonism distinguishes PD 142676 from other anticholinesterases, and may be useful in treating the cognitive dysfunction of AD and produce fewer peripheral side effects.
ESTHER : Emmerling_1994_Mol.Neurobiol_9_93
PubMedSearch : Emmerling_1994_Mol.Neurobiol_9_93
PubMedID: 7888109

Title : Characterization of muscarinic agonists in recombinant cell lines - Schwarz_1993_Life.Sci_52(5-6)_465
Author(s) : Schwarz RD , Davis RE , Jaen JC , Spencer CJ , Tecle H , Thomas AJ
Ref : Life Sciences , 52 :465 , 1993
Abstract : Using recombinant CHO cells that express Hm1-Hm5 receptors, reference muscarinic agonists have been characterized with respect to their activity in receptor binding and second messenger assays. In whole cell [3H]-N-methyl scopolamine binding, no agonist was found to be truly subtype selective, although some showed marked differences between several of the subtypes (e.g. m1 vs. m2). As a functional index of receptor activation, phosphatidyl-inositol (PI) turnover was measured for m1, m3, and m5 receptors while inhibition of forskolin-stimulated cAMP accumulation was measured for m2 and m4 receptors. Both full and partial agonists were delineated in PI turnover, but all agonists showed similar responses on cAMP. Alkylation studies with propylbenzylcholine mustard showed that both efficacy and potency were markedly affected in the functional assays by the number of free receptors. Thus, receptor reserve appears to play a major role in the determination of subtype selectivity for agonists using functional measures. Even with these limitations, however, the use of transformed cell lines is playing a pivotal role in the discovery of selective agonists.
ESTHER : Schwarz_1993_Life.Sci_52(5-6)_465
PubMedSearch : Schwarz_1993_Life.Sci_52(5-6)_465
PubMedID: 8382764

Title : Synthesis and SAR of bulky 1-azabicyclo[2.2.1]-3-one oximes as muscarinic receptor subtype selective agonists - Tecle_1993_Life.Sci_52(5-6)_505
Author(s) : Tecle H , Lauffer DJ , Mirzadegan T , Moos WH , Moreland DW , Pavia MR , Schwarz RD , Davis RE
Ref : Life Sciences , 52 :505 , 1993
Abstract : The synthesis of a series of potent and efficacious 1-azabicyclo[2.2.1]heptan-3-one oxime muscarinic agonists is described. The oximes have extended appendages designed to span the cavity defined by the seven transmembrane helices of the muscarinic receptor. Some members of the series are selective for receptors of the m1 subtype. One such oxime, 31, shows affinity and functional selectivity for m1 over m2, m3, and m4 muscarinic receptor types.
ESTHER : Tecle_1993_Life.Sci_52(5-6)_505
PubMedSearch : Tecle_1993_Life.Sci_52(5-6)_505
PubMedID: 8382765

Title : Cholinergic agents: effect of methyl substitution in a series of arecoline derivatives on binding to muscarinic acetylcholine receptors - Moos_1992_J.Pharm.Sci_81_1015
Author(s) : Moos WH , Bergmeier SC , Coughenour LL , Davis RE , Hershenson FM , Kester JA , McKee JS , Marriott JG , Schwarz RD , Tecle H , Thomas AJ
Ref : J Pharm Sci , 81 :1015 , 1992
Abstract : Arecoline, arecaidine, and a series of derivatives, differing by the presence or absence of methyl groups at positions on the periphery of the molecule, were prepared, and their binding to muscarinic acetylcholine receptors was tested. On the basis of this study, muscarinic agonism for arecoline series is governed by strict structure-activity relationships, as previously observed for other agonist series. Only minor changes in nitrogen substitution were tolerated in the present series of arecoline derivatives.
ESTHER : Moos_1992_J.Pharm.Sci_81_1015
PubMedSearch : Moos_1992_J.Pharm.Sci_81_1015
PubMedID: 1432612

Title : Next generation tacrine -
Author(s) : Schwarz RD , Davis RE , Gracon S , Hoover T , Moos WH , Pavia MR
Ref : Neurobiology of Aging , 12 :185 , 1991
PubMedID: 2052133

Title : Poster: Pharmacology of tacrine: comparisons with other cholinesterase inhibitors -
Author(s) : Davis RE , Coughenour LL , Dudley DT , Pugsley TA , Schwarz RD , Moos WH
Ref : In: Cholinesterases: Structure, Function, Mechanism, Genetics, and Cell Biology , (Massoulie J, Barnard EA, Chatonnet A, Bacou F, Doctor BP, Quinn DM) American Chemical Society, Washington, DC :346 , 1991
PubMedID:

Title : Poster: Inhibition of rat acetyl- and butyrylcholinesterase activity by tacrine and related aminoacridines -
Author(s) : Schwarz RD , Spencer CJ , Davis RE , Moos WH , Pavia MR , Thomas AJ
Ref : In: Cholinesterases: Structure, Function, Mechanism, Genetics, and Cell Biology , (Massoulie J, Barnard EA, Chatonnet A, Bacou F, Doctor BP, Quinn DM) American Chemical Society, Washington, DC :343 , 1991
PubMedID:

Title : Poster: CI-969: An orally active muscarinic receptor agonist related to arecoline -
Author(s) : Pavia MR , Schwarz AD , Coughenour LL , Davis RE , Dudley DT , Moos WH , Pugsley TA , Tecle H , Clark CA
Ref : Trends in Pharmacological Sciences , Suppl :100 , 1989
PubMedID: