Abstract：
:The N-demethylation of 1-(N-methyl-N-trideuteriomethylamino)-3-phenylpropane (1) by rodent liver homogenates was studied. The ratio of 1-trideuteriomethylamino-3-phenylpropane (2)/1-methylamino-3-phenylpropane (3) was determined by gc-ms. The ratio of 2/3 in the product of N-demethylation of 1 by liver homogenate from phenobarbital-treated rats was 1.31 and from untreated rats was 1.32, and the differences between the two groups were not statistically significant. The ratio of 2/3 in the product obtained from N-demethylation of 1 by liver homogenates from mice was 1.45. The ratio of 2/3 of greater than unity indicates the presence of a kinetic primary isotopes effect in the enzymatic N-demethylation reaction. This effect is exclusive of the secondary isotope effects on the amino nitrogen. The presence of this primary isotope effect indicates that the cleavage of the C-H bond of the N-methyl group is a rate-limiting step in the N-demethylation of tertiary amines by rodent microsomal enzymes.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Abdel-Monem MMdoi
10.1021/jm00238a021keywords:
subject
Has Abstractpub_date
1975-04-01 00:00:00pages
427-30issue
4eissn
0022-2623issn
1520-4804journal_volume
18pub_type
杂志文章abstract：:The sodium ion site is an allosteric site conserved among many G protein-coupled receptors (GPCRs). Amiloride 1 and 5-(N,N-hexamethylene)amiloride 2 (HMA) supposedly bind in this sodium ion site and can influence orthosteric ligand binding. The availability of a high-resolution X-ray crystal structure of the human ade...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.6b00142
更新日期：2016-05-26 00:00:00
abstract：:Neurodegenerative diseases represent a challenge for biomedical research due to their high prevalence and lack of mechanism-based treatments. Because of the complex pathology of neurodegenerative disorders, multifunctional drugs have been increasingly recognized as potential treatments. We identified homobivalent γ-ca...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.5b00958
更新日期：2015-08-27 00:00:00
abstract：:Reports of a high-affinity ligand for E-selectin, sialyl di-Lewis(x) (sLe(x)Le(x), 1), motivated us to incorporate modifications to previously reported biphenyl-based inhibitors that would provide additional interactions with the protein. These compounds were assayed for the ability to inhibit the binding of sialyl Le...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm9704917
更新日期：1998-03-26 00:00:00
abstract：:Insulin secretion by pancreatic β-cells in response to glucose or other secretagogues is tightly coupled to membrane potential. Various studies have highlighted the prospect of enhancing insulin secretion in a glucose-dependent manner by blocking voltage-gated potassium channels (K(v)) and calcium-activated potassium ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm401904q
更新日期：2014-03-27 00:00:00
abstract：:Ketanserin is the prototypic 5-HT2 serotonin antagonist; although it has been an important tool for the study of serotonin pharmacology, it has had relatively little impact on drug design because remarkably little is known about its structure-affinity relationships. Furthermore, ketanserin also binds at 5-HT1C recepto...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00104a017
更新日期：1992-12-25 00:00:00
abstract：:Wnt proteins regulate various cellular functions and serve distinct roles in normal development throughout life. Wnt signaling is dysregulated in various diseases including cancers. Porcupine (PORCN) is a membrane-bound O-acyltransferase that palmitoleates the Wnts and hence is essential for their secretion and functi...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.5b00507
更新日期：2015-08-13 00:00:00
abstract：:Substituted 6-anilinouracils were found to be potent inhibitors of the replication-specific enzyme, DNA polymerase III, from Bacillus subtilis. Inhibition potency was maximized by inclusion of small alkyl groups or halogens in the meta and para positions of the phenyl ring; polar substituents decreased activity consi...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00175a007
更新日期：1980-01-01 00:00:00
abstract：:Three ellipticine-estradiol conjugates were synthesized in an effort to target the cytotoxicity of ellipticine to estrogen-receptor positive cells. The three conjugates were prepared with linker chains extending from the 17 alpha position of the estradiol to N-2 (compound 3), N-6 (compound 4), and C-9 (compound 5) pos...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm9602930
更新日期：1996-08-16 00:00:00
abstract：:We describe here a classical molecular modeling exercise that was carried out to provide a basis for the design of novel antagonist ligands of the CCR2 receptor. Using a theoretical model of the CCR2 receptor, docking studies were carried out to define plausible binding modes for the various known antagonist ligands, ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm030862l
更新日期：2003-09-11 00:00:00
abstract：:The cytotoxicity of oxysterols was systematically studied in tumor and normal cells. Synthetic strategies to prepare this library included oxidations at ring B and a new method to yield 6β-hemiphthalates directly from Δ(5)-steroids. Most oxysterols were cytotoxic and showed selectivity toward cancer cells, LAMA-84 cel...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm1007769
更新日期：2010-11-11 00:00:00
abstract：:Novel antibiotics are urgently needed to combat the rise of infections due to drug-resistant microorganisms. Numerous natural nucleosides and their synthetically modified analogues have been reported to have moderate to good antibiotic activity against different bacterial and fungal strains. Nucleoside-based compounds...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章,评审
doi：10.1021/acs.jmedchem.6b00325
更新日期：2016-12-08 00:00:00
abstract：:A high-throughput screen at 100 microM inhibitor concentration for the BACE-1 enzyme revealed a novel spiropiperidine iminohydantoin aspartyl protease inhibitor template. An X-ray cocrystal structure with BACE-1 revealed a novel mode of binding whereby the inhibitor interacts with the catalytic aspartates via bridging...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm800914n
更新日期：2008-10-23 00:00:00
abstract：:Evidence indicating that modifications at the 5- and 10-positions of classical folic acid antimetabolites lead to compounds with favorable differential membrane transport in tumor vs. normal proliferative tissue prompted an investigation of 5-alkyl-5-deaza analogues. 2-Amino-4-methyl-3,5-pyridinedicarbonitrile, prepar...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00156a029
更新日期：1986-06-01 00:00:00
abstract：:The synthesis and pharmacological activity of a new series of hexahydro-2H-pyrano[3,2-c]quinoline derivatives as potent σ1 receptor (σ1R) ligands are reported. This family, which does not contain the highly basic amino group usually present in other σ1R ligands, showed high selectivity over the σ2 receptor (σ2R). The ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm400181k
更新日期：2013-05-09 00:00:00
abstract：:Thiolactomycin inhibits bacterial cell growth through inhibition of the beta-ketoacyl-ACP synthase activity of type II fatty acid synthases. The effect of modifications of the 5-position isoprenoid side chain on both IC(50) and MIC were determined. Synthesis and screening of a structurally diverse set of 5-position an...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm050825p
更新日期：2006-01-12 00:00:00
abstract：:Treatment of a methanolic solution of 4-hydroxy-1-beta-D-ribofuranosyl-2-pyridinone (3-deazauridine, 1) with diazomethane gave 2-methoxy-1-beta-D-ribofuranosyl-4-pyridinone (2) and 4-methoxy-1-beta-D-ribofuranosyl-2-pyridinone (3a) in an approximate ratio of 1:2. Analogous treatment of 1 with diazomethane in the prese...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00245a005
更新日期：1975-11-01 00:00:00
abstract：:Bridging chemical and biological space is the key to drug discovery and development. Typically, cheminformatics methods operate under the assumption that similar chemicals have similar biological activity. Ideally then, one could predict a drug's biological function(s) given only its chemical structure by similarity s...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm060902w
更新日期：2006-11-16 00:00:00
abstract：:Based on the X-ray cocrystal structure of the Tang-Ghosh heptapeptide inhibitor 1 (OM00-3), a series of macroheterocyclic analogues were designed and synthesized. Analogues containing dithia, dioxa, oxathia, and carbathia macrocycles were synthesized by methods relying on ring-closing olefin metathesis for the dioxa a...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm060154a
更新日期：2006-07-27 00:00:00
abstract：:The definitive diagnosis of Alzheimer's disease (AD) requires the detection of amyloid plaques in postmortem brain. Although the amount of fibrillar amyloid roughly correlates with the severity of symptoms at the time of death, the temporal relationship between amyloid deposition, neuronal loss, and cognitive decline ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm990103w
更新日期：1999-07-29 00:00:00
abstract：:MMP-12 plays a significant role in airway inflammation and remodeling. Increased expression and production of MMP-12 have been observed in the lungs of asthmatic patients. Compound 27 was identified as a potent and selective MMP-12 inhibitor possessing good physicochemical properties. In pharmacological studies, the c...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm900809r
更新日期：2009-09-10 00:00:00
abstract：:Benzimidazoles carrying the 2-hydroxy-3-(isopropylamino)propoxy side chain at either the C-4 or C-5 ring positions were synthesized and investigated for beta-adrenergic blocking activity. Both compounds demonstrated beta2 selectivity when evaluated in guinea pig atrial and tracheal preparations. The C-4 isomer was 17 ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00188a019
更新日期：1979-02-01 00:00:00
abstract：:Phthalocyanines (Pcs) are a class of photosensitizers (PSs) with a strong tendency to aggregate in aqueous environment, which has a negative influence on their photosensitizing ability in photodynamic therapy. Pcs with either peripheral or axial solketal substituents, that is, ZnPc(sol)8 and Si(sol)2Pc, respectively, ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm061136w
更新日期：2007-04-05 00:00:00
abstract：:Treatment of the sodium salt of 4-chloro-2-(methylthio)pyrrolo[2,3-d]pyrimidine (2) with (2-acetoxyethoxy)methyl bromide (3) has provided 4-chloro-2-(methylthio)-7[(2-acetoxyethoxy)methyl]pyrrolo[2,3- d]pyrimidine (4). Ammonolysis of 4 at room temperature gave 4-chloro-2-(methylthio)-7-[(2-hydroxyethoxy)methyl]pyrrolo...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00403a005
更新日期：1988-08-01 00:00:00
abstract：:The synthesis, biological evaluation, and structure-activity relationships of a series of N-phenyl heteroaryl-fused isothiazolones are described. These isothiazolones have been shown to exhibit potent, dose-dependent inhibition of IL-1 beta-induced breakdown of proteoglycan in a cartilage organ culture assay. This eff...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00045a012
更新日期：1994-09-16 00:00:00
abstract：:The tremendous therapeutic potential of voltage-gated sodium channels (Na(v)s) has been the subject of many studies in the past and is of intense interest today. Na(v)1.7 channels in particular have received much attention recently because of strong genetic validation of their involvement in nociception. Here we summa...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章,评审
doi：10.1021/jm501981g
更新日期：2015-09-24 00:00:00
abstract：:Botulinum neurotoxins (BoNT) are the most potent toxins known and a significant bioterrorist threat. Few small molecule compounds have been identified that are active in cell-based or animal models, potentially due to toxin enzyme plasticity. Here we screened commercially available quinolinols, as well as synthesized ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm4012164
更新日期：2014-02-13 00:00:00
abstract：:Whereas the 2-propyl- and 2-butyl-5,6-(methylenedioxy)indene calcium antagonists reversed the spasmogenic action of several agonists including PGF2alpha and acetylcholine at 5 X 10(-5) to 10(-4) M on the rat ileum, the corresponding 5,6-dimethoxy analogues exhibited spasmogenic activity at higher concentration (10(-4)...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00210a028
更新日期：1978-12-01 00:00:00
abstract：:The antitumor prodrug temozolomide is compromised by its dependence for activity on DNA mismatch repair (MMR) and the repair of the chemosensitive DNA lesion, O6-methylguanine (O6-MeG), by O6-methylguanine-DNA-methyltransferase (E.C. 2.1.1.63, MGMT). Tumor response is also dependent on wild-type p53. Novel 3-(2-anilin...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm401121k
更新日期：2013-09-12 00:00:00
abstract：:We disclose optimization efforts based on the novel non-nucleoside adenosine deaminase (ADA) inhibitor, 4 (K(i) = 680 nM). Structure-based drug design utilizing the crystal structure of the 4/ADA complex led to discovery of 5 (K(i) = 11 nM, BA = 30% in rats). Furthermore, from metabolic considerations, we discovered t...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0499559
更新日期：2004-05-20 00:00:00
abstract：:A series of natural epimers of alpha-homonojirimycin and its N-alkylated derivatives have been prepared to investigate the contribution of the different chiral centers and conformation of the specificity and potency of inhibition of glycosidases. These epimers and N-alkylated derivatives are alpha-homonojirimycin (1),...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm970836l
更新日期：1998-07-02 00:00:00
