Abstract:
:To learn more about the binding conformation of phencyclidine (PCP) and to arrive at analogues of higher affinity, which may serve as noncompetitive N-methyl-D-aspartate receptor antagonists, eight optically pure PCP analogues were designed with the aid of computer. These compounds represent conformationally constrained versions of PCP in which the motion of the phenyl ring is frozen, thus allowing a determination of the orientation of the phenyl ring relevant to binding. The analogues were synthesized by a Diels-Alder strategy and tested in a radioligand binding assay to evaluate their affinity for the PCP binding site of the N-methyl-D-aspartate receptor complex. One of the analogues was found to bind with nanomolar affinity (IC50 = 19 nM) and to be 73-fold more potent in binding than its enantiomer. These results, which further elucidate the structural determinants of high affinity binding, should aid both in the design of higher affinity molecular probes of the PCP binding site and in the discovery of potential neuroprotective agents.
journal_name
Mol Pharmacoljournal_title
Molecular pharmacologyauthors
Kozikowski AP,Pang YPsubject
Has Abstractpub_date
1990-03-01 00:00:00pages
352-7issue
3eissn
0026-895Xissn
1521-0111journal_volume
37pub_type
杂志文章abstract::Both human ether-à-go-go-related gene (hERG1) and the closely related human ether-à-go-go (hEAG1) channel are aberrantly expressed in a large proportion of human cancers. In the present study, we demonstrate that transfection of hERG1 into mouse fibroblasts is sufficient to induce many features characteristic of malig...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.113.091439
更新日期:2014-08-01 00:00:00
abstract::The hexapeptide [pGlu6,Pro9]substance P (SP)6-11, septide, has been shown to be an agonist as potent as SP in eliciting smooth muscle contraction in several in vitro preparations, while being a poor competitor of labeled SP binding. These results, as well as other pharmacological data, have suggested the existence of ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1994-02-01 00:00:00
abstract::The 5-hydroxytryptamine3 receptor 5-HT3R has been implicated in gut and cardiac motility and in behavioral disorders. Characteristics of 5-HT3Rs appear to be heterogeneous among species, but human 5-HT3R cDNA has not been identified. We isolated a cDNA encoding 5-HT3R from human hippocampus. The mouse 5-HT3R gene has ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1995-09-01 00:00:00
abstract::The aptamer mechanism of action involves the direct interaction of oligonucleotide with protein and is responsible for the biological effects of many pharmacologically active oligodeoxynucleotides. In the work reported here, we have determined the effects of aptamers on the secondary, tertiary, and quaternary structur...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1998-05-01 00:00:00
abstract::α-Conotoxins are subtype-selective nicotinic acetylcholine receptor (nAChR) antagonists. Although potent α3β2 nAChR-selective α-conotoxins have been identified, currently characterized α-conotoxins show no or only weak affinity for α4β2 nAChRs, which are, besides α7 receptors, the most abundant nAChRs in the mammalian...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.112.078683
更新日期:2012-10-01 00:00:00
abstract::The μ-opioid receptor gene undergoes extensive alternative splicing to generate an array of splice variants. One group of splice variants excludes the first transmembrane (TM) domain and contains six TM domains. These 6TM variants are essential for the action of a novel class of analgesic drugs, including 3-iodobenzoy...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.120.119453
更新日期:2020-10-01 00:00:00
abstract::Accumulated evidence suggests that dopamine and dopamine D1 agonists can activate phospholipase C in both brain and peripheral tissue. The receptor that mediates the hydrolysis of phosphoinositides has not been identified. The cloned dopamine D1A receptor that is generally thought to be linked to adenylyl cyclase, has...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.51.1.6
更新日期:1997-01-01 00:00:00
abstract::Nod2 is an intracellular pattern recognition receptor that detects a conserved moiety of bacterial peptidoglycan and subsequently activates proinflammatory signaling pathways. Mutations in Nod2 have been implicated to be linked to inflammatory granulomatous disorders, such as Crohn's disease and Blau syndrome. Many ph...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.108.046169
更新日期:2008-07-01 00:00:00
abstract::For a series of antitumor-active 5-substituted 9-aminoacridine-4-carboxamide topoisomerase II poisons, we have used X-ray crystallography and stopped-flow spectrophotometry to explore relationships between DNA binding kinetics, biological activity, and the structures of their DNA complexes. The structure of 5-F-9-amin...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.58.3.649
更新日期:2000-09-01 00:00:00
abstract::This study describes experiments investigating the mechanism of activation of A1 adenosine receptors. Isolated rat fat cells were used as a cellular model. The A1 receptors of these cells were covalently labeled with the agonist photoaffinity label R-2-azido-N6-p-hydroxyphenylisopropyladenosine. The covalent incorpora...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1986-10-01 00:00:00
abstract::A family of five cholinergic muscarinic receptor genes (m1, m2, m3, m4, and m5) has recently been identified and cloned. In order to investigate the pharmacological properties of the individual muscarinic receptors, we have transfected each of these genes into Chinese hamster ovary cells (CHO-K1) and have established ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1989-04-01 00:00:00
abstract::There is no approved means to prevent the toxic actions of cocaine. Cocaine esterase (CocE) is found in a rhodococcal strain of bacteria that grows in the rhizosphere soil around the coca plant and has been found to hydrolyze cocaine in vitro. The esteratic activity of CocE (0.1-1.0 mg, i.v.) was characterized and con...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.106.025999
更新日期:2006-12-01 00:00:00
abstract::Newly synthesized tocainide analogs were tested for their state-dependent affinity and use-dependent behavior on sodium currents (INa) of adult skeletal muscle fibers by means of the Vaseline-gap voltage clamp method. The drugs had the pharmacophore amino group constrained in position alpha [N-(2,6-dimethylphenyl)pyrr...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.64.4.932
更新日期:2003-10-01 00:00:00
abstract::Nuclear receptors play important roles in the maintenance of the endocrine system, regulation of organ differentiation, and fetal development. Endocrine disruptors exert their adverse effects by disrupting the endocrine system via various mechanisms. To assess the effects of endocrine disruptors on nuclear receptors, ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.104.008409
更新日期:2005-03-01 00:00:00
abstract::A conjugate molecule was synthesized by linking the DNA-intercalative antitumor drug 4'-(9-acridinylamino)methanesulfon-manisidide (mAMSA) via a 4-carboxamide side chain to a dipyrrolecarboxamide moiety structurally related to the minor groove-binding antibiotic netropsin. The molecule (netropsin/ mAMSA) behaves as a ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1997-03-01 00:00:00
abstract::P2X receptors are trimeric membrane proteins. When they bind extracellular ATP, a conformational change occurs that opens a transmembrane ion channel. The ATP-binding pocket is formed in a cleft between two subunits, and a critical amino acid residue for ATP contact is Lys⁶⁹ (P2X2 numbering). In the present work, we s...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.112.080903
更新日期:2012-10-01 00:00:00
abstract::Aldosterone synthase (AS) regulates blood volume by synthesizing the mineralocorticoid aldosterone. Overproduction of aldosterone in the adrenal gland can lead to hypertension, a major cause of heart disease and stroke. Aldosterone production depends upon stimulation of AS expression by the renin-angiotensin system, w...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.111.076471
更新日期:2012-03-01 00:00:00
abstract::Cytokines are thought to cause the depression of cytochrome P-450 (CYP)-associated drug metabolism in humans during inflammation and infection. We have examined the role of five cytokines, i.e., interleukin-1 beta, interleukin-4, interleukin-6, tumor necrosis factor-alpha, and interferon-gamma, on the expression of CY...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1993-10-01 00:00:00
abstract::Cell-penetrating peptides are amphipathic or cationic oligopeptides able to transport covalently attached cargoes across cell membranes. Peptide aptamers are polypeptide fragments of endogenous proteins that mimic and thus perturb interactions with other cellular proteins. Combining aptamer and CPP technology can gene...
journal_title:Molecular pharmacology
pub_type: 评论,杂志文章
doi:10.1124/mol.105.011429
更新日期:2005-04-01 00:00:00
abstract::Studies of the biochemical mechanisms evoked by conventional treatments for neoplastic diseases point to apoptosis as a key process for elimination of unwanted cells. Although the pathways through which chemotherapeutics promote cell death remain largely unknown, caspase proteases play a central role in the induction ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.53.3.446
更新日期:1998-03-01 00:00:00
abstract::Most anticancer drugs have their origin in traditional medicinal plants. We describe here a flavone, 5,3'-dihydroxy-3,6,7,8,4'-pentamethoxyflavone (PMF), from the leaves of the Thai plant Gardenia obtusifolia, that has anti-inflammatory and anticancer potential. Because the nuclear factor-κB (NF-κB) pathway is linked ...
journal_title:Molecular pharmacology
pub_type: 杂志文章,收录出版
doi:10.1124/mol.110.067512
更新日期:2011-02-01 00:00:00
abstract::Peroxisome proliferator-activated receptor δ (PPARδ) has been implicated in vascular pathophysiology. However, its functions in atherogenic changes of the vascular wall have not been fully elucidated. PPARδ activated by GW501516 (2-[2-methyl-4-[[4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl]methylsulfanyl]ph...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.116.104679
更新日期:2016-11-01 00:00:00
abstract::We present a mechanism for agonist-promoted alpha(2A)-adrenergic receptor (alpha(2A)-AR) activation based on structural, pharmacological, and theoretical evidence of the interactions between phenethylamine ligands and alpha(2A)-AR. In this study, we have: 1) isolated enantiomerically pure phenethylamines that differ b...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.59.5.1343
更新日期:2001-05-01 00:00:00
abstract::Molecular chaperone heat shock protein 90 (HSP90) is involved in oncogenic signaling pathways including epithelial-mesenchymal transition (EMT), a key process in tumor initiation, progression, metastasis, and chemoresistance. The molecular mechanisms underlying the involvement of HSP90 in EMT are still under investiga...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.119.116137
更新日期:2019-08-01 00:00:00
abstract::In the human lymphocyte, desensitization of the beta-adrenergic receptor-adenylate cyclase complex is associated with sequestration of the receptor as well as a change in photolabeling of beta-receptor proteins. Thus, desensitization of the lymphocyte beta-adrenergic receptor-adenylate cyclase system is associated wit...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1986-11-01 00:00:00
abstract::Prior studies indicate that adenosine and the adenosine A2A receptor play a role in hepatic fibrosis by a mechanism that has been proposed to involve direct stimulation of hepatic stellate cells (HSCs). The objective of this study was to determine whether primary hepatic stellate cells produce collagen in response to ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.107.038760
更新日期:2007-12-01 00:00:00
abstract::High-affinity glycine transport in neurons and glial cells is a primary means of inactivating synaptic glycine. We have synthesized a potent selective inhibitor of glycine transporter 1 (GlyT1), and characterized its activity using a quail fibroblast cell line (QT6). The glycine transporters GlyT1A, GlyT1B, GlyT1C, an...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.60.6.1414
更新日期:2001-12-01 00:00:00
abstract::Bupropion is an atypical antidepressant that also has usefulness as a smoking-cessation aid. Because hydroxybupropion, a major metabolite of bupropion, is believed to contribute to its antidepressant activity, this metabolite may also contribute to the smoking-cessation properties of bupropion. This study investigated...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.104.001313
更新日期:2004-09-01 00:00:00
abstract::2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) was found to activate protein kinases under cell- and nucleus-free conditions in isolated C57 mouse liver cytosol (100,000 x g supernatant). This action of TCDD was found to be aryl hydrocarbon receptor (AHR) dependent, concentration dependent, and inhibited by genistein, a t...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.52.4.667
更新日期:1997-10-01 00:00:00
abstract::The L-type amino acid transporter 1 (LAT1) is an Na(+)-independent neutral amino acid transporter subserving the amino acid transport system L. Because of its broad substrate selectivity, system L has been proposed to be responsible for the permeation of amino acid-related drugs through the plasma membrane. To underst...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.61.4.729
更新日期:2002-04-01 00:00:00