Return of D4 Dopamine Receptor Antagonists in Drug Discovery.


: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.


J Med Chem


Lindsley CW,Hopkins CR




Has Abstract


2017-09-14 00:00:00












  • Exploiting the Tolerant Region I of the Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI) Binding Pocket: Discovery of Potent Diarylpyrimidine-Typed HIV-1 NNRTIs against Wild-Type and E138K Mutant Virus with Significantly Improved Water Solubility an

    abstract::Diarylpyrimidine derivatives (DAPYs) exhibit robust anti-HIV-1 potency, although they have been compromised by E138K variant and severe side-effects and been suffering from poor water solubility. In the present work, hydrophilic morpholine or methylsulfonyl and sulfamide-substituted piperazine/piperidines were introdu...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Huang B,Chen W,Zhao T,Li Z,Jiang X,Ginex T,Vílchez D,Luque FJ,Kang D,Gao P,Zhang J,Tian Y,Daelemans D,De Clercq E,Pannecouque C,Zhan P,Liu X

    更新日期:2019-02-28 00:00:00

  • Inhibitors of cholesterol biosynthesis. 2. Hypocholesterolemic and antioxidant activities of benzopyran and tetrahydronaphthalene analogues of the tocotrienols.

    abstract::Tocotrienols exhibit antioxidant and cholesterol-biosynthesis-inhibitory activities and may be of value as antiatherosclerotic agents. The mechanism of their hypolipidemic action involves posttranscriptional suppression of HMG-CoA reductase (HMGR) in a manner mimicking the action of putative non-sterol feedback inhibi...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Pearce BC,Parker RA,Deason ME,Dischino DD,Gillespie E,Qureshi AA,Volk K,Wright JJ

    更新日期:1994-02-18 00:00:00

  • Adenosine mimetics as inhibitors of NAD+-dependent histone deacetylases, from kinase to sirtuin inhibition.

    abstract::NAD+-dependent histone deacetylases, sirtuins, cleave acetyl groups from lysines of histones and other proteins to regulate their activity. Identification of potent selective inhibitors would help to elucidate sirtuin biology and could lead to useful therapeutic agents. NAD+ has an adenosine moiety that is also presen...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Trapp J,Jochum A,Meier R,Saunders L,Marshall B,Kunick C,Verdin E,Goekjian P,Sippl W,Jung M

    更新日期:2006-12-14 00:00:00

  • Synthesis of prenyl pyrophosphonates as new potent phosphoantigens inducing selective activation of human Vgamma9Vdelta2 T lymphocytes.

    abstract::Gamma9delta2T cells represent the most abundant population of human blood gammadeltaT lymphocytes. They produce and promote strong cytotoxic activity against many pathogens that are implicated in several human infectious diseases. Their activation requires their exposure to small phosphorus-containing antigens in the ...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Zgani I,Menut C,Seman M,Gallois V,Laffont V,Liautard J,Liautard JP,Criton M,Montero JL

    更新日期:2004-08-26 00:00:00

  • X-ray Structure Analysis of Indazolium trans-[Tetrachlorobis(1H-indazole)ruthenate(III)] (KP1019) Bound to Human Serum Albumin Reveals Two Ruthenium Binding Sites and Provides Insights into the Drug Binding Mechanism.

    abstract::Ruthenium(III) complexes are promising candidates for anticancer drugs, especially the clinically studied indazolium trans-[tetrachlorobis(1H-indazole)ruthenate(III)] (KP1019) and its analogue sodium trans-[tetrachlorobis(1H-indazole)ruthenate(III)] (NKP-1339). Several studies have emphasized the likely role of human ...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Bijelic A,Theiner S,Keppler BK,Rompel A

    更新日期:2016-06-23 00:00:00

  • Podophyllotoxin analogs. 1. Synthesis and biological evaluation of certain trans-2-aryl-trans-6-hydroxymethyl-3-cyclohexenecarboxylic acid gamma-lactones as antimitotic agents.

    abstract::A series of cis and trans bicyclic lactones was prepared as congeners of podophyllotoxin (1) and evaluated as antimitotic agents both in cell cultures grown in vitro and in an in vitro protein binding assay. All compounds displayed insignificant activity-a result which may reflect insufficient structural similarity to...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Smissman EE,Murray RJ,McChesney JD,Houston LL,Pazdernik TL

    更新日期:1976-01-01 00:00:00

  • Synthesis and biological activity of 5'-substituted 5-fluoropyrimidine nucleosides.

    abstract::5'-Deoxy-5-fluorouridine (5'-dFUrd, 1) possesses a significantly higher chemotherapeutic index than other fluoropyrimidines as a result of its being selectivity cleaved in tumors to 5-fluorouracil (FUra) by uridine phosphorylase. Because 1 is a relatively poor substrate for this enzyme, we synthesized a series of 5'-d...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Ajmera S,Danenberg PV

    更新日期:1982-08-01 00:00:00

  • Thromboxane synthetase inhibitors and antihypertensive agents. 1. N-[(1H-imidazol-1-yl)alkyl]aryl amides and N-[(1H-1,2,4-triazol-1-yl)alkyl]aryl amides.

    abstract::The title compounds were prepared to investigate their potential as thromboxane synthetase inhibitors as well as antihypertensive agents. Imidazoles VIII and triazoles X were prepared to examine the effects of aromatic substitution, chain length, and heterocycle substitution upon biological activity. Imidazoles VIII a...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Wright WB Jr,Press JB,Chan PS,Marsico JW,Haug MF,Lucas J,Tauber J,Tomcufcik AS

    更新日期:1986-04-01 00:00:00

  • Discovery of Hydrolysis-Resistant Isoindoline N-Acyl Amino Acid Analogues that Stimulate Mitochondrial Respiration.

    abstract::N-Acyl amino acids directly bind mitochondria and function as endogenous uncouplers of UCP1-independent respiration. We found that administration of N-acyl amino acids to mice improves glucose homeostasis and increases energy expenditure, indicating that this pathway might be useful for treating obesity and associated...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Lin H,Long JZ,Roche AM,Svensson KJ,Dou FY,Chang MR,Strutzenberg T,Ruiz C,Cameron MD,Novick SJ,Berdan CA,Louie SM,Nomura DK,Spiegelman BM,Griffin PR,Kamenecka TM

    更新日期:2018-04-12 00:00:00

  • 1,3-Dialkyl-8-(p-sulfophenyl)xanthines: potent water-soluble antagonists for A1- and A2-adenosine receptors.

    abstract::A series of 8-(substituted phenyl) derivatives of theophylline and other 1,3-dialkylxanthines were evaluated for potency and selectivity as antagonists at A1- and A2-adenosine receptors in brain tissue. Theophylline has a similar potency (Ki = 14 microM) at both A1 and A2 receptors. 8-Phenyltheophylline is 25-35-fold ...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Daly JW,Padgett W,Shamim MT,Butts-Lamb P,Waters J

    更新日期:1985-04-01 00:00:00

  • Synthesis and Pharmacological Evaluation of Triazolopyrimidinone Derivatives as Noncompetitive, Intracellular Antagonists for CC Chemokine Receptors 2 and 5.

    abstract::CC chemokine receptors 2 (CCR2) and 5 (CCR5) are involved in many inflammatory diseases; however, most CCR2 and CCR5 clinical candidates have been unsuccessful. (Pre)clinical evidence suggests that dual CCR2/CCR5 inhibition might be more effective in the treatment of such multifactorial diseases. In this regard, the h...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Ortiz Zacarías NV,van Veldhoven JPD,den Hollander LS,Dogan B,Openy J,Hsiao YY,Lenselink EB,Heitman LH,IJzerman AP

    更新日期:2019-12-26 00:00:00

  • Preparation and analgesic properties of amino acid derivatives of (-)-5,9 alpha-diethyl-2'-hydroxybenzomorphan.

    abstract::The N-arginyl derivative of methionine-enkephalin (fragment 60-65 of beta-lipotropin) has been shown to be equiactive with the parent pentapeptide, despite the fact that the tyrosine amino group in this compound has been neutralized by the formation of an amide linkage. A series of N-(amino acid) derivatives of (-)-5,...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Bélanger PC,Scheigetz J,Young RN,Charleson SE,Hudgin RL,Engelhardt EL

    更新日期:1981-11-01 00:00:00

  • 1-imidazolyl(alkyl)-substituted di- and tetrahydroquinolines and analogues: syntheses and evaluation of dual inhibitors of thromboxane A(2) synthase and aromatase.

    abstract::A series of 1-imidazolyl(alkyl)-substituted quinoline, isoquinoline, naphthalene, benzo[b]furan, and benzo[b]thiophene derivatives was synthesized as dual inhibitors of thromboxane A(2) synthase (P450 TxA(2)) and aromatase (P450 arom). Dual inhibition of these enzymes could be a novel strategy for the treatment of mam...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Jacobs C,Frotscher M,Dannhardt G,Hartmann RW

    更新日期:2000-05-04 00:00:00

  • Structure-activity relationships at the 5-position of thiolactomycin: an intact (5R)-isoprene unit is required for activity against the condensing enzymes from Mycobacterium tuberculosis and Escherichia coli.

    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


    authors: Kim P,Zhang YM,Shenoy G,Nguyen QA,Boshoff HI,Manjunatha UH,Goodwin MB,Lonsdale J,Price AC,Miller DJ,Duncan K,White SW,Rock CO,Barry CE 3rd,Dowd CS

    更新日期:2006-01-12 00:00:00

  • Bivalent diketopiperazine-based tropomysin receptor kinase C (TrkC) antagonists.

    abstract::Bivalent molecules containing two beta-turn mimics with side chains that correspond to hot-spots on the neurotrophin NT-3 were prepared. Binding assays showed the mimetics to be selective TrkC ligands, and biological assays showed one mimetic to be an antagonist of the TrkC receptor. ...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Liu J,Brahimi F,Saragovi HU,Burgess K

    更新日期:2010-07-08 00:00:00

  • Anti-HIV agents that selectively target retroviral nucleocapsid protein zinc fingers without affecting cellular zinc finger proteins.

    abstract::Agents that target the two highly conserved Zn fingers of the human immunodeficiency virus (HIV) nucleocapsid p7 (NCp7) protein are under development as antivirals. These agents covalently modify Zn-coordinating cysteine thiolates of the fingers, causing Zn ejection, loss of native protein structure and nucleic acid b...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Huang M,Maynard A,Turpin JA,Graham L,Janini GM,Covell DG,Rice WG

    更新日期:1998-04-23 00:00:00

  • Discovery of inhibitors to block interactions of HIV-1 integrase with human LEDGF/p75 via structure-based virtual screening and bioassays.

    abstract::This study aims to identify inhibitors that bind at the interface of HIV-1 integrase (IN) and human LEDGF/p75, which represents a novel target for anti-HIV therapy. To date, only a few such inhibitors have been reported. Here structure-based virtual screening was performed to search for the inhibitors from an in-house...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Hu G,Li X,Zhang X,Li Y,Ma L,Yang LM,Liu G,Li W,Huang J,Shen X,Hu L,Zheng YT,Tang Y

    更新日期:2012-11-26 00:00:00

  • Antioxidant-based inhibitors of leukotriene biosynthesis. The discovery of 6-[1-[2-(hydroxymethyl)phenyl]-1-propen-3-yl]-2,3-dihydro-5- benzofuranol, a potent topical antiinflammatory agent.

    abstract::The leukotrienes, metabolites of arachidonic acid produced through the action of the enzyme 5-lipoxygenase, are important mediators of immediate hypersensitivity and inflammation. Among the variety of diseases in which the leukotrienes may play a symptomatic or causative role is the dermatological condition psoriasis,...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Hammond ML,Zambias RA,Chang MN,Jensen NP,McDonald J,Thompson K,Boulton DA,Kopka IE,Hand KM,Opas EE

    更新日期:1990-03-01 00:00:00

  • Synthesis, chemistry, and antineoplastic activity of alpha-halopyridinium salts: potential pyridone prodrugs of acylated vinylogous carbinolamine tumor inhibitors.

    abstract::A series of 4- and 5-[2,3-dihydro-6,7-bis[[(N-alkylcarbamoyl)oxy]methyl]-1H-pyrrol izin-5- yl]-2-halopyridinium iodides were synthesized. The rates of hydrolysis of the alpha-halopyridinium salts to the corresponding pyridones, and the reactivities of the carbamate moieties were studied as a function of pH, buffer com...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Anderson WK,Dean DC,Endo T

    更新日期:1990-06-01 00:00:00

  • Syntheses and photodynamic activities of novel trisulfonated zinc phthalocyanine derivatives.

    abstract::The synthesis of water-soluble, unsymmetrical, trisulfonated zinc phthalocyanines (ZnPcS3) as single products of the ring expansion of boron tri(4-sulfo)subphthalocyanine (SubPc) is reported. The novel, water-soluble trisulfo-SubPcB(OH) was prepared via hydrolysis of the tris(4-chlorosulfonyl)SubPcB(Br) which in turn ...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Kudrevich S,Brasseur N,La Madeleine C,Gilbert S,van Lier JE

    更新日期:1997-11-21 00:00:00

  • Differentiating the Pharmacodynamics and Toxicology of Macrolide and Ketolide Antibiotics.

    abstract::This is a review of the macrolide and ketolide field focusing on differentiating the pharmacodynamics and especially the toxicology of the macrolides and ketolides. We emphasize the diversity in pharmacodynamics and toxicity of the macrolides and ketolides, resulting from even small structural changes, which makes it ...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Fernandes P,Pereira D,Watkins PB,Bertrand D

    更新日期:2020-06-25 00:00:00

  • Structure-activity relationship studies for the peptide portion of the bladder epithelial cell antiproliferative factor from interstitial cystitis patients.

    abstract::We performed comprehensive structure-activity relationship (SAR) studies on the peptide portion of antiproliferative factor (APF), a sialylated frizzled-8 related glycopeptide that inhibits normal bladder epithelial and urothelial carcinoma cell proliferation. Glycopeptide derivatives were synthesized by solid-phase m...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Kaczmarek P,Keay SK,Tocci GM,Koch KR,Zhang CO,Barchi JJ Jr,Grkovic D,Guo L,Michejda CJ

    更新日期:2008-10-09 00:00:00

  • Novel purine nitrile derived inhibitors of the cysteine protease cathepsin K.

    abstract::Starting from the high-throughput screening hit 1a, novel cathepsin K inhibitors have been developed based on a purine scaffold. High-resolution X-ray structures of several derivatives have revealed the binding mode of these unique cysteine protease inhibitors. ...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Altmann E,Cowan-Jacob SW,Missbach M

    更新日期:2004-11-18 00:00:00

  • Synthesis and Pharmacological Evaluation of Noscapine-Inspired 5-Substituted Tetrahydroisoquinolines as Cytotoxic Agents.

    abstract::A series of 5-substituted tetrahydroisoquinolines was synthesized via a 10-step linear synthesis to assess whether replacement of noscapine's southern isobenzofuranone with other moieties resulted in retained cytotoxic activity. One such molecule, 18g, bearing a para-methoxybenzyl functionality with N-ethylcarbamoyl s...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Devine SM,Yong C,Amenuvegbe D,Aurelio L,Muthiah D,Pouton C,Callaghan R,Capuano B,Scammells PJ

    更新日期:2018-09-27 00:00:00

  • Potent and selective farnesyl transferase inhibitors.

    abstract::We recently described a novel series of CA(1)A(2)X peptidomimetics as farnesyl transferase inhibitors (FTIs). These compounds possess an N-(4-piperidinyl)benzamide scaffold mimicking A(1)A(2) residue. Extensive exploration of structure--activity relationships revealed that replacement of cysteine by substituted benzyl...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Millet R,Domarkas J,Houssin R,Gilleron P,Goossens JF,Chavatte P,Logé C,Pommery N,Pommery J,Hénichart JP

    更新日期:2004-12-30 00:00:00

  • Renin inhibitors containing psi[CH2O] pseudopeptide inserts.

    abstract::Renin inhibitors 2-4 with the D-Lys renin inhibitory peptide (RIP) sequence, but containing Leu psi[CH2O]Ala (2), Leu psi[CH2O]Val (3), and Leu psi[CH2O]Leu (4) at the P1-P1' site, were of a comparable potency to RIP. N-Terminal Boc-protected inhibitors containing Pro psi[CH2O]Phe in positions P4-P3 were potent inhibi...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: TenBrink RE,Pals DT,Harris DW,Johnson GA

    更新日期:1988-03-01 00:00:00

  • Computer-aided design of selective COX-2 inhibitors: comparative molecular field analysis, comparative molecular similarity indices analysis, and docking studies of some 1,2-diarylimidazole derivatives.

    abstract::Comparative molecular field analysis and comparative molecular similarity indices analysis were performed on 114 analogues of 1,2-diarylimidazole to optimize their cyclooxygenase-2 (COX-2) selective antiinflammatory activities. These studies produced models with high correlation coefficients and good predictive abilit...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Desiraju GR,Gopalakrishnan B,Jetti RK,Nagaraju A,Raveendra D,Sarma JA,Sobhia ME,Thilagavathi R

    更新日期:2002-10-24 00:00:00

  • Two analogues of fenarimol show curative activity in an experimental model of Chagas disease.

    abstract::Chagas disease, caused by the protozoan parasite Trypanosoma cruzi (T. cruzi), is an increasing threat to global health. Available medicines were introduced over 40 years ago, have undesirable side effects, and give equivocal results of cure in the chronic stage of the disease. We report the development of two compoun...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Keenan M,Chaplin JH,Alexander PW,Abbott MJ,Best WM,Khong A,Botero A,Perez C,Cornwall S,Thompson RA,White KL,Shackleford DM,Koltun M,Chiu FC,Morizzi J,Ryan E,Campbell M,von Geldern TW,Scandale I,Chatelain E,Charman

    更新日期:2013-12-27 00:00:00

  • Further studies on the Dmt-Tic pharmacophore: hydrophobic substituents at the C-terminus endow delta antagonists to manifest mu agonism or mu antagonism.

    abstract::Twenty N- and/or C-modified Dmt-Tic analogues yielded similar K(i) values with either [(3)H]DPDPE (delta(1) agonist) or [(3)H]N, N(Me)(2)-Dmt-Tic-OH (delta antagonist). N-Methylation enhanced delta antagonism while N-piperidine-1-yl, N-pyrrolidine-1-yl, and N-pyrrole-1-yl were detrimental. Dmt-Tic-X (X = -NHNH(2), -NH...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Salvadori S,Guerrini R,Balboni G,Bianchi C,Bryant SD,Cooper PS,Lazarus LH

    更新日期:1999-12-02 00:00:00

  • Quantitative structure-activity studies on monoamine oxidase inhibitors.

    abstract::Quantitative structure-activity studies were carried out on a series of N-isopropylaryl hydrazides which inhibits monoamine oxidase (MAO). The inhibitory potencies of these compounds of MAO were found to correlate with the electron-withdrawing capacity of the aryl ring substituents as estimated by both empirical Hamme...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Johnson CL

    更新日期:1976-05-01 00:00:00