Abstract：
:The dopamine D4 receptor garnered a great deal of interest in the early 1990s when studies showed the atypical antipsychotic clozapine possessed higher affinity for D4, relative to other dopamine receptor subtypes, and that this activity might underlie the unique clinical efficacy of clozapine. Unfortunately, D4 antagonists that were developed for schizophrenia failed in the clinic. Thus, D4 fell out of favor as a therapeutic target, and work in this area was silent for decades. Recently, D4 ligands with improved selectivity for D4 against not only D1-3,5 but also other biogenic amine targets have emerged, and D4 is once again in the spotlight as a novel target for both addiction and Parkinson's disease (PD), as well as other emerging diseases. This report will review the historical data for D4, review the known D4 ligands, and then highlight new data supporting a role for D4 inhibition in addiction, PD, and cancer.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Lindsley CW,Hopkins CRdoi
10.1021/acs.jmedchem.7b00151subject
Has Abstractpub_date
2017-09-14 00:00:00pages
7233-7243issue
17eissn
0022-2623issn
1520-4804journal_volume
60pub_type
杂志文章,评审abstract：:A series of 4(6)-(benzyloxy)-2,6(4)-diamino-5-(nitro or nitroso)pyrimidine derivatives and analogues of which 4(6)-benzyloxy groups were replaced with a (2-, 3-, or 4-fluorobenzyl)oxy or (2-, 3-, or 4-pyridylmethyl)oxy group, was synthesized. The abilities of these compounds to inhibit human O6-alkylguanine-DNA alkylt...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm970363i
更新日期：1998-02-12 00:00:00
abstract：:Inhibitor of secreted frizzled related protein-1 (sFRP-1) would be a novel potential osteogenic agent, since loss of sFRP-1 affects osteoblast proliferation, differentiation, and activity, resulting in improved bone mineral density, quality, and strength. We have identified small molecule diarylsulfone sulfonamide der...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm801069w
更新日期：2008-12-25 00:00:00
abstract：:A novel series of fully synthetic 8-azatetracyclines was prepared and evaluated for antibacterial activity. Compounds were identified that overcome both efflux (tet(K)) and ribosomal protection (tet(M)) tetracycline resistance mechanisms and are active against Gram-positive and Gram-negative organisms. Two compounds w...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm1015389
更新日期：2011-03-10 00:00:00
abstract：:The antiproliferative activity of the 14 isomeric monoxylosylated dihydroxynaphthalenes has been tested in vitro toward normal HFL-1 and 3T3 A31 cells as well as transformed T24 and 3T3 SV40 cells. The antiproliferative effect toward HFL-1 cells was correlated with the polarity of the compounds. However, in the case o...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0512488
更新日期：2006-03-23 00:00:00
abstract：:By applying a novel cell- and caspase-based HTS assay, 2-amino-3-cyano-7-(dimethylamino)-4-(3-methoxy-4,5-methylenedioxyphenyl)-4H-chromene (1a) has been identified as a potent apoptosis inducer. Compound 1a was found to induce nuclear fragmentation and PARP cleavage, as well as to arrest cells at the G(2)/M stage and...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm049640t
更新日期：2004-12-02 00:00:00
abstract：:A structure-guided design approach using a homology model of Plasmodium falciparum calcium-dependent protein kinase 1 (PfCDPK1) was used to improve the potency of a series of imidazopyridazine inhibitors as potential antimalarial agents. This resulted in high affinity compounds with PfCDPK1 enzyme IC50 values less tha...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm500342d
更新日期：2014-04-24 00:00:00
abstract：:A series of 80 7-(het)aryl- and 7-ethynyl-7-deazapurine ribonucleosides bearing a methoxy, methylsulfanyl, methylamino, dimethylamino, methyl, or oxo group at position 6, or 2,6-disubstituted derivatives bearing a methyl or amino group at position 2, were prepared, and the biological activity of the compounds was stud...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm4018948
更新日期：2014-02-13 00:00:00
abstract：:The synthesis and biological evaluation of a series of 2-substituted 5-phenyl-1,4-benzodiazepines, structurally related to tifluadom (5), the only benzodiazepine that acts simultaneously as a kappa-opioid agonist and a cholecystokinin-A (CCK-A) antagonist, are reported. The radioligand binding models used in these stu...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm950423p
更新日期：1996-02-16 00:00:00
abstract：:alpha-Fluoromethyl amino acids are enzyme-activated irreversible inhibitors of amino acid decarboxylases. Aromatic L-amino acid decarboxylase (AADC) is the enzyme responsible for the final step in the biosynthesis of both dopamine and serotonin via decarboxylation of L-dopa and 5-hydroxy-L-tryptophan, respectively. Ou...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00055a001
更新日期：1993-02-05 00:00:00
abstract：:A six-stage stereoselective synthesis of indanyl-7-(3'-pyridyl)-(3R,6R,7R)-2,5-diketopiperazines oxytocin antagonists from indene is described. SAR studies involving mono- and disubstitution in the 3'-pyridyl ring and variation of the 3-isobutyl group gave potent compounds (pK(i) > 9.0) with good aqueous solubility. E...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm201287w
更新日期：2012-01-26 00:00:00
abstract：:A series of novel 2-[(4-phenylpiperazin-1-yl)methyl]imidazoazines and aza-analogues were prepared and screened at selected dopamine, serotonin, and adrenergic receptor subtypes. 2-Substituted imidazopyridines and pyridazines presented high affinities and selectivities for D4 dopamine receptors. Whereas functional expe...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm060166w
更新日期：2006-06-29 00:00:00
abstract：:To understand how chloroquine (CQ) enhances transgene expression in polycation-based, nonviral gene delivery systems, a number of CQ analogues with variations in the aliphatic amino side chain or in the aromatic ring are synthesized and investigated. Our studies indicate that the aliphatic amino moiety of CQ is essent...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm060736s
更新日期：2006-11-02 00:00:00
abstract：:Glucose flux through glucokinase (GK) controls insulin release from the pancreas in response to high glucose concentrations. Glucose flux through GK also contributes to reducing hepatic glucose output. Because many individuals with type 2 diabetes appear to have an inadequacy or defect in one or both of these processe...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm401116k
更新日期：2013-10-10 00:00:00
abstract：:An inactin-anesthetized rat cardiovascular (CV) assay was employed in a screening mode to triage multiple classes of melanin-concentrating hormone receptor 1 (MCHr1) antagonists. Lead identification was based on a compound profile producing high drug concentration in both plasma (>40 microM) and brain (>20 microg/g) w...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0512286
更新日期：2006-04-06 00:00:00
abstract：:We have derivatized Momordica saponins (MS) I and II through their coupling at C3 glucuronic acid site with dodecylamine. The derivatives show significantly different immunostimulant activity profiles from their respective natural parent saponins. In particular, adjuvant VSA-1 (5), the derivative of MS I, potentiates ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.9b01511
更新日期：2019-11-14 00:00:00
abstract：:We have identified RWJ-671818 (8) as a novel, low molecular weight, orally active inhibitor of human alpha-thrombin (K(i) = 1.3 nM) that is potentially useful for the acute and chronic treatment of venous and arterial thrombosis. In a rat deep venous thrombosis model used to assess antithrombotic efficacy, oral admini...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章,随机对照试验
doi：10.1021/jm901802n
更新日期：2010-02-25 00:00:00
abstract：:Vitamin D receptor (VDR) antagonists prevent the VDR activation function helix 12 from folding into its active conformation, thus affecting coactivator recruitment and antagonizing the transcriptional regulation induced by 1α,25-dihydroxyvitamin D3. Here, we report the crystal structure of the zebrafish VDR ligand-bin...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.0c00656
更新日期：2020-09-10 00:00:00
abstract：:Adenosine derivatives developed to activate adenosine receptors (ARs) revealed micromolar activity at serotonin 5HT2B and 5HT2C receptors (5HTRs). We explored the structure-activity relationship at 5HT2Rs and modeled receptor interactions in order to optimize affinity and simultaneously reduce AR affinity. Depending o...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.6b01183
更新日期：2016-12-22 00:00:00
abstract：:A series of cis- and trans-dihydroxycotahydrobenzo[f]quinoline congeners of dopamine has been prepared, in which the N substitutent is H, ethyl, or n-propyl. The trans isomers include the dopamine moiety held rigidly in an antiperiplanar diposition which is believed to be necessary for certian central and peripheral d...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00190a002
更新日期：1979-04-01 00:00:00
abstract：:Necrosis is the main mode of cell death, which leads to multiple clinical conditions affecting hundreds of millions of people worldwide. Its molecular mechanisms are poorly understood, hampering therapeutics development. Here, we identify key proteolytic activities essential for necrosis using various biochemical appr...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.0c01683
更新日期：2021-01-31 00:00:00
abstract：:An approach to the development of new anticandidal drugs is described that employs peptides as carriers of toxic agents into cells. 5-Flurorcytosine (5-FC) was chosen as a toxic agent with which to prepare 5-FC-peptide conjugates as models to test the carrier proposal. Model compounds were synthesized and then tested ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00195a019
更新日期：1979-09-01 00:00:00
abstract：:A series of (E)-phenoxyacrylic amide derivatives were synthesized and evaluated as hypoxia inducible factor (HIF) 1α inhibitors. The present structure-activity relationship study on this series identified the morpholinoethyl containing ester 4p as a potent inhibitor of HIF-1α under hypoxic conditions (IC50=0.12 μM in ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm301419d
更新日期：2012-12-13 00:00:00
abstract：:In a previously described chimeric peptide, we reported that the multifunctional opioid/neuropeptide FF (NPFF) receptor agonist 0 (BN-9) produced antinociception for 1.5 h after supraspinal administration. Herein, four cyclic disulfide analogs containing l- and/or d-type cysteine at positions 2 and 5 were synthesized....
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.0c01367
更新日期：2020-12-24 00:00:00
abstract：:Membrane-associated serine protease matriptase has been implicated in human diseases and might be a drug target. In the present study, a novel class of matriptase inhibitors targeting zymogen activation is developed by a combination of the screening of compound library using a cell-based matriptase activation assay an...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm200920s
更新日期：2011-11-10 00:00:00
abstract：:A number of analogues of ibotenic acid [(RS)-3-hydroxy-5- isoxazoleglycine ] were synthesized; they were tested as excitants on neurons in the cat spinal cord, by using microelectrophoretic techniques, and as inhibitors of the binding of kainic acid (KA) in vitro, by using synaptic membranes prepared from rat brains. ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00371a005
更新日期：1984-05-01 00:00:00
abstract：:A series of 7(8 leads to 11 alpha)abeo steroids was synthesized by a modification of the previously described total synthesis of this class of compounds and evaluated for biological activity. In general, there was a marked reduction in the relative binding affinities of these compounds for the rabbit uterus estrogen a...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00214a017
更新日期：1977-04-01 00:00:00
abstract：:Basic side chains determine the pharmacology of selective estrogen receptor modulators such as tamoxifen or raloxifene. In this study we tried to turn the hormonal profile of (4R,5S)/(4S,5R)-4,5-bis(4-hydroxyphenyl)-2-imidazolines from agonistic to antagonistic by introduction of a dimethylaminoethane, a piperidin-1-y...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm040855c
更新日期：2005-01-27 00:00:00
abstract：:New N-alkylanilinoquinazoline derivatives 5, 12, 20, and 22 have been prepared from 4-chloro-6,7-dimethoxyquinazoline 3, 4-chloro-6,7-methylenedioxyquinazoline 19, and commercially available anilines. Differents classes of compounds substituted by an aryloxygroup (6a-c, 16a,b, and 17a,b), (aminophenyl)ureas (12a,b and...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm1009605
更新日期：2010-11-25 00:00:00
abstract：:The solid-phase reductive alkylation of the Lys side chain in positions 6 (D) and 8 (L) and position 8 alone of the LH-RH antagonist [N-Ac-D-Nal,D-Ph2,3,D-Arg6,Phe7,D-Ala10]LH-RH was investigated in an attempt to reduce the histamine-releasing activity inherent to most potent antagonists while retaining high antiovula...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00393a038
更新日期：1987-10-01 00:00:00
abstract：:A series of 3-descladinosyl-2,3-anhydro-6-O-methylerythromycin A 11, 12-carbamate analogues have been synthesized and evaluated for antibacterial activity. These compounds were found to be potent antibacterial agents against Gram-positive organisms in vitro, many having MIC values below 1 microg/mL for the macrolide-s...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm970547x
更新日期：1998-05-07 00:00:00
