Abstract:
:In a continuation of studies directed toward characterizing the hydrophilic pocket within the aromatic ring binding region of the active site of phenylethanolamine N-methyltransferase (PNMT), 5-, 6-, 7-, and 8-hydroxy-1,2,3,4-tetrahydroisoquinoline were prepared and evaluated as substrates and inhibitors of PNMT. In order to discern the necessity of an acidic hydrogen for interaction at this pocket the corresponding methyl ethers were also evaluated. The enhanced affinity of 7-hydroxy-1,2,3,4-tetrahydroisoquinoline (16) versus tetrahydroisoquinoline (13) itself indicates that a hydrophilic pocket exists off of carbon C7 in bound tetrahydroisoquinolines. The diminished affinity of the corresponding methyl ether is consistent with a requirement for the acidic hydrogen of 16 for interaction of the aromatic hydroxyl at this site. From the relative activities of the other regioisomeric aromatic hydroxyl-substituted tetrahydroisoquinolines, their corresponding methyl ethers, and 6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, it appears that the hydrophilic pocket is spatially compact with respect to bound tetrahydroisoquinolines and is surrounded by larger areas of lipophilic character. To allow a comparison of the results of this study with previous data on bound beta-phenylethylamines, the methyl ethers of 5-, 6-, 7-, and 8-hydroxy-exo-2-aminobenzonorbornene and of 5- and 6-hydroxy-anti-9-aminobenzonorbornene were also evaluated for their activity as substrates and inhibitors for PNMT. The results of this study are in agreement with previous findings for bound beta-phenylethylamines and support the conclusion that the natural substrate for PNMT, norepinephrine, has a different active site binding orientation than most known substrates and competitive inhibitors of the enzyme.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Sall DJ,Grunewald GLdoi
10.1021/jm00395a006subject
Has Abstractpub_date
1987-12-01 00:00:00pages
2208-16issue
12eissn
0022-2623issn
1520-4804journal_volume
30pub_type
杂志文章abstract::Prodrug-mediated utilization of the cytochrome P450 (CYP) 1A1 to obtain the selective release of potent anticancer products within cancer tissues is a promising approach in chemotherapy. We herein report the rationale, preparation, biological evaluation, and mechanism of action of phenyl 4-(2-oxo-3-alkylimidazolidin-1...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.7b00343
更新日期:2017-06-22 00:00:00
abstract::A novel series of substituted (pyrroloamino)pyridines was synthesized, and the compounds were evaluated for cholinomimetic-like properties in vitro (inhibition of [3H]quinuclidinyl benzilate binding) and in vivo (reversal of scopolamine-induced dementia) as potential agents for the treatment of Alzheimer's disease. Co...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm950644v
更新日期:1996-01-19 00:00:00
abstract::Thirty compounds related to the selective dopamine-autoreceptor agonist 3-(3-hydroxyphenyl)-N-n-propylpiperidine have been synthesized and tested for central dopamine-autoreceptor stimulating activity. The 3-(3-hydroxyphenyl)piperidine moiety seems indispensable for high potency and selectivity. Introduction of an add...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00144a021
更新日期:1981-12-01 00:00:00
abstract::Treatment of a protected 9-(5, 6-dideoxy-beta-D-ribo-hex-5-ynofuranosyl)adenine derivative with silver nitrate and N-iodosuccinimide (NIS) and deprotection gave the 6'-iodo acetylenic nucleoside analogue 3c. Halogenation of 3-O-benzoyl-5,6-dideoxy-1, 2-O-isopropylidene-alpha-D-ribo-hex-5-enofuranose gave 6-halo acetyl...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm980163m
更新日期:1998-09-24 00:00:00
abstract::Some 2-aryloxymethyl-2,3,5,6-tetrahydro-1,4-oxazines have been shown to possess marked antidepressant activity. The 1,4-oxazines were synthesized by lithium aluminum hydride reduction of the readily available 6-aryloxymethyl-2,3,5,6-tetrahydro-1,4-oxazin-3-ones. High antidepressant activity was associated with ortho s...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00240a009
更新日期:1975-06-01 00:00:00
abstract::We have designed and synthesized eight compounds 2-9 which incorporate various amino acid residues in positions 17, 18, and 21 of the glucagon molecule: 2, [Lys17]glucagon amide; 3, [Lys18]glucagon amide; 4, [Nle17,Lys18,Glu21]glucagon amide; 5, [Orn17,18, Glu21]glucagon amide; 6, [d-Arg17]glucagon; 7, [d-Arg18]glucag...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm980084a
更新日期:1998-07-16 00:00:00
abstract::The effect of substitution in the acyclic structure of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)-thymine (HEPT) on anti-HIV-1 activity was investigated by synthesizing a series of deoxy analogs and related compounds. Preparation of 1-[(2-alkyloxyethoxy)methyl]-6- (phenylthio)thymine (2-4) derivatives was carried out ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00103a009
更新日期:1992-12-11 00:00:00
abstract::The ortho hydroxy/methyl, hydroxy/hydroxymethyl, hydroxy/formyl, and hydroxy/carboxy substitution patterns, some of which confer dopaminergic agonist effects upon 2-aminotetralin ring systems, have been incorporated into beta-phenethylamine, 2-aminoindan, and trans-octahydrobenzo[f]quinoline rings. Certain of the 2-am...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00160a036
更新日期:1986-10-01 00:00:00
abstract::A series of nitrocoumarin and nitrochromene derivatives have been prepared and shown to inhibit the phosphatidylinositol-specific phospholipase C(PLC)(IC50 < 10 micrograms/mL) isolated from human melanoma. The inhibition of PLC by nitrocoumarin 4a was time-dependent and irreversible. The inhibition of PLC was shown to...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00040a016
更新日期:1994-07-08 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::A series of bisalkamine esters, bis-basic ethers, and bis-basic ketones of carbazole, N-ethylcarbazole, dibenzofuran, and dibenzothiophene was synthesized and evaluated for antiviral activity. The series also included two bis-basic alkanes of N-ethylcarbazole and one bis-basic carboxamide of dibenzofuran. Structure-ac...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00213a011
更新日期:1977-03-01 00:00:00
abstract::Sepsis, which is a systemic inflammatory response that follows a bacterial infection, has a high mortality rate and limited therapeutic options. Here we show that the antimicrobial peptide OH-CATH30, which naturally occurs in snake, selectively regulates the innate immune response to protect mice from lethal sepsis. T...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm401134n
更新日期:2013-11-27 00:00:00
abstract::PABA/NO is a diazeniumdiolate of structure Me(2)NN(O)=NOAr (where Ar is a 5-substituted-2,4-dinitrophenyl ring whose 5-substituent is N-methyl-p-aminobenzoic acid). It has shown activity against human ovarian cancer xenografts in mice rivaling that of cisplatin, but it is poorly soluble and relatively unstable in wate...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm050700k
更新日期:2006-02-09 00:00:00
abstract::Inhibition of histone deacetylases (HDACs) leads to growth arrest, differentiation, or apoptosis of tumor cell lines, suggesting HDACs as promising targets for cancer therapy. At present, only one HDAC inhibitor (HDACi) is used in therapy: suberoylanilide hydroxamic acid (SAHA). Here, we describe the synthesis and bio...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm901561u
更新日期:2010-03-11 00:00:00
abstract::Two complete and two partial structure-activity relationship scans of the active fragment of human growth hormone-releasing hormone, [Nle27]-hGHRH(1-29)-NH2, have identified potent agonists in vitro. Single-point replacement of each amino acid by alanine led to the identification of [Ala8]-, [Ala9]-, [Ala15]- (Felix e...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm970618s
更新日期:1998-02-26 00:00:00
abstract::There has been significant interest in developing a transient receptor potential A1 (TRPA1) antagonist for the treatment of pain due to a wealth of data implicating its role in pain pathways. Despite this, identification of a potent small molecule tool possessing pharmacokinetic properties allowing for robust in vivo ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.6b00039
更新日期:2016-03-24 00:00:00
abstract::Type II beta-turn mimics and polyproline II helix mimics based upon diastereoisomeric 5.6.5 spiro bicyclic scaffolds have provided two pairs of Pro-Leu-Gly-NH(2) (PLG) peptidomimetics with contrasting dopamine receptor modulating activities. Compounds 1a and 3a were found to be positive allosteric modulators of the do...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm801575w
更新日期:2009-04-09 00:00:00
abstract::TYK2 is an emerging drug target for various human autoimmune diseases. However, discovery of selective TYK2 inhibitor over other JAK family members (i.e., JAK1, 2, 3) by targeting the catalytically active site (Janus Homologue 1 (JH1) domain) is challenging. This Viewpoint discusses the discovery of a series of N-meth...
journal_title:Journal of medicinal chemistry
pub_type: 评论,杂志文章
doi:10.1021/acs.jmedchem.9b01612
更新日期:2019-10-24 00:00:00
abstract::Screening of our internal chemical collection against the neuropeptide Y5 (NPY Y5) receptor allowed the identification of a benzoxazine derivative 5f as a hit that showed moderate affinity (IC(50) = 300 nM). With the aim of improving the in vitro potency, a series of 2-benzoxazinone derivatives have been synthesized a...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm049599u
更新日期:2005-03-24 00:00:00
abstract::A series of quinolone and naphthyridine antibacterial agents possessing as the C7-heterocycle bicyclic 2,5-diazabicyclo[n.2.m]alkanes, where n = 2, 3 and m = 1, 2, and a series including 4-aminopiperidine and 3-amino-8-azabicyclo[3.2.1]octanes have been prepared and evaluated in vitro and in vivo for antibacterial act...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00106a029
更新日期:1991-02-01 00:00:00
abstract::Aberrant RET kinase signaling plays critical roles in several human cancers such as thyroid carcinoma. The gatekeeper mutants (V804L or V804M) of RET are resistant to currently approved RET inhibitors such as cabozantinib and vandetanib. We, for the first time, report a highly selective and extremely potent RET inhibi...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.5b01522
更新日期:2016-01-14 00:00:00
abstract::As part of our studies to develop novel retinoids with increased affinity and selectivity for the retinoid X receptor (RXR) subfamily, we have designed and synthesized a series of (E,E,E)-7-(1,2,3, 4-tetrahydroquinolin-6-yl)-7-alkyl-6-fluoro-3-methylhepta-2, 4, 6-trienoic acid derivatives. These tetrahydroquinolines, ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm980058c
更新日期:1998-08-13 00:00:00
abstract::Three phosphapeptides designed to mimic two distinct tetrahedral intermediates formed during either the synthesis or hydrolysis of glutathionylspermidine (Gsp) were synthesized and evaluated as inhibitors of the bifunctional enzyme Gsp synthetase/amidase. While the polyamine-containing phosphapeptides were determined ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm970414b
更新日期:1997-11-07 00:00:00
abstract::Previously, we reported the thiourea antagonists 2a and 2b as potent and high affinity TRPV1 antagonists. For further optimization of the lead compounds, a series of their amide and alpha-substituted amide surrogates were investigated and novel chiral N-(2-benzyl-3-pivaloyloxypropyl) 2-[4-(methylsulfonylamino)phenyl]p...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm701049p
更新日期:2008-01-10 00:00:00
abstract::In recent papers (Catarzi, D.; et al. J. Med. Chem. 2000, 43, 3824-3826; 2001, 44, 3157-3165) we reported chemical and biological studies on 4,5-dihydro-4-oxo-1,2,4-triazolo[1,5-a]quinoxaline-2-carboxylates (TQXs) bearing different nitrogen-containing heterocycles at position-8. In particular, from these studies it em...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm030906q
更新日期:2004-01-01 00:00:00
abstract::A novel series of 16-substituted-4-azasteroids has been identified as potential tissue-selective androgen receptor modulators. These ligands display potent hAR binding and agonist activity, low virilizing potential, and good pharmacokinetic profiles in dogs. On the basis of its in vitro profile, 21 was evaluated in th...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm900880r
更新日期:2009-08-13 00:00:00
abstract::A series of 1-thia analogues of the pyrrolizine bis(carbamate) 9 (NSC-278214), namely 5-aryl-2,3-dihydropyrrolo-[2,1-b]thiazole-6,7-dimethanol 6,7-bis(isopropylcarbamates) (7a-d), were prepared by multistep syntheses from the proline analogue thiazolidine-2-carboxylic acid. The compounds were tested for growth inhibit...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00402a030
更新日期:1988-07-01 00:00:00
abstract::The enantiomers of the aminothiazole analogues of the known dopaminergic agonists apomorphine (1) and 2-aminohydroxytetralin (2) have been prepared. The absolute configurations of the enantiomers of 2,6-diaminotetrahydrobenzothiazole have been established by X-ray crystallographic analysis. Dopamine (DA) autoreceptor ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00386a009
更新日期:1987-03-01 00:00:00
abstract::The JmjC oxygenases catalyze the N-demethylation of N(ε)-methyl lysine residues in histones and are current therapeutic targets. A set of human 2-oxoglutarate analogues were screened using a unified assay platform for JmjC demethylases and related oxygenases. Results led to the finding that daminozide (N-(dimethylamin...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm300677j
更新日期:2012-07-26 00:00:00
abstract::Peptide mimetics of the RGDF sequence in which Arg-Gly has been replaced with 5-(4-amidinophenyl)pentanoyl mimetic has led to a 1000-fold increase in inhibitory potency over the natural RGDF ligand. The guanidine residue of the arginine may be involved in a reinforced ionic interaction with a carboxylate of the recept...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00065a003
更新日期:1993-06-25 00:00:00