α2-adrenoceptor antagonists: synthesis, pharmacological evaluation, and molecular modeling investigation of pyridinoguanidine, pyridino-2-aminoimidazoline and their derivatives.


:We have previously identified phenylguanidine and phenyl-2-aminoimidazoline compounds as high affinity ligands with conflicting functional activity at the α2-adrenoceptor, a G-protein-coupled receptor with relevance in several neuropsychiatric conditions. In this paper we describe the design, synthesis, and pharmacological evaluation of a new series of pyridine derivatives [para substituted 2- and 3-guanidino and 2- and 3-(2-aminoimidazolino)pyridines, disubstituted 2-guanidinopyridines and N-substituted-2-amino-1,4-dihydroquinazolines] that were found to be antagonists/inverse agonists of the α2-adrenoceptor. Furthermore, the compounds exert their effects at the α2-adrenoceptor both in vitro in human prefrontal cortex tissue and in vivo in rat brain as shown by microdialysis experiments. We also provide a docking study at the α2A- and α2C-adrenoceptor subtypes demonstrating the structural features required for high affinity binding to the receptor.


J Med Chem


Kelly B,McMullan M,Muguruza C,Ortega JE,Meana JJ,Callado LF,Rozas I




Has Abstract


2015-01-22 00:00:00












  • Synthesis and antitumor activity of tropolone derivatives. 3.

    abstract::As part of a study on the antitumor activities of tropolone derivatives prepared from hinokitiol, which naturally occurs in the plants of Chamaecyparis species, effects of aromatic substituents of alpha,alpha-bis(7-hydroxy-5-isopropyltropon-2-yl)toluenes on the activity were examined. Several of the compounds showed h...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Yamato M,Hashigaki K,Kokubu N,Tashiro T,Tsuruo T

    更新日期:1986-07-01 00:00:00

  • Total synthesis and pharmacological characterization of solomonsterol A, a potent marine pregnane-X-receptor agonist endowed with anti-inflammatory activity.

    abstract::Recently, we reported the identification of a novel class of pregnane-X-receptor (PXR) agonists, solomonsterols A and B, isolated from the marine sponge Theonella swinhoei. Preliminary pharmacological studies demonstrated that these natural compounds are potential leads for the treatment of human disorders characteriz...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Sepe V,Ummarino R,D'Auria MV,Mencarelli A,D'Amore C,Renga B,Zampella A,Fiorucci S

    更新日期:2011-07-14 00:00:00

  • New N-n-propyl-substituted 3-aryl- and 3-cyclohexylpiperidines as partial agonists at the D4 dopamine receptor.

    abstract::We have previously reported that compounds dimethyl-substituted on the phenyl ring of N-n-propyl-3-phenylpiperidines (PPEs) have a high (nM) affinity and selectivity toward the D(4) dopamine receptor (D(4) DAR) with m,p-dimethyl PPE (1) having the highest affinity and selectivity. In the present paper we have investig...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Macchia M,Cervetto L,Demontis GC,Longoni B,Minutolo F,Orlandini E,Ortore G,Papi C,Sbrana A,Macchia B

    更新日期:2003-01-02 00:00:00

  • Cannabinoids. 1. 1-Amino- and 1-mercapto-7,8,9,10-tetrahydro-6H-dibenzo [b,d]pyrans.

    abstract::A series of 1-amino- and 1-mercapto-7,8,9,10-tetrahydro-6H-dibenzo[b,d]pyrans was synthesized and subsequently evaluated in three rodent test systems for CNS activity. The structure-activity data generated indicate that, in general, a change of the 1-hydroxy group to an amine results in a retention of pharmacological ...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Matsumoto K,Stark P,Meister RG

    更新日期:1977-01-01 00:00:00

  • 2-[(4-phenylpiperazin-1-yl)methyl]imidazo(di)azines as selective D4-ligands. Induction of penile erection by 2-[4-(2-methoxyphenyl)piperazin-1-ylmethyl]imidazo[1,2-a]pyridine (PIP3EA), a potent and selective D4 partial agonist.

    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


    authors: Enguehard-Gueiffier C,Hübner H,El Hakmaoui A,Allouchi H,Gmeiner P,Argiolas A,Melis MR,Gueiffier A

    更新日期:2006-06-29 00:00:00

  • Rational Design of Dimeric Lysine N-Alkylamides as Potent and Broad-Spectrum Antibacterial Agents.

    abstract::Antibiotic resistance is one of the biggest threats to public health, and new antibacterial agents hence are in an urgent need to combat infectious diseases caused by multidrug-resistant (MDR) pathogens. Utilizing dimerization strategy, we rationally designed and efficiently synthesized a new series of small molecule ...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Niu Y,Wang M,Cao Y,Nimmagadda A,Hu J,Wu Y,Cai J,Ye XS

    更新日期:2018-04-12 00:00:00

  • alpha-Keto amide inhibitors of aminopeptidases.

    abstract::The design and synthesis of 3-amino-2-oxo-4-phenylbutanoic acid amides (alpha-keto amides), a new class of aminopeptidase inhibitor, are described. These compounds, illustrated by the Phe-Leu analogue 2, are effective inhibitors of arginyl aminopeptidase (Ki = 1.5 microM), cytosol aminopeptidase (Ki = 1.0 microM), and...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Ocain TD,Rich DH

    更新日期:1992-02-07 00:00:00

  • Structure-activity relationships and binding mode of styrylquinolines as potent inhibitors of HIV-1 integrase and replication of HIV-1 in cell culture.

    abstract::Our prior studies showed that polyhydroxylated styrylquinolines are potent HIV-1 integrase (IN) inhibitors that block the replication of HIV-1 in cell culture at nontoxic concentrations. To explore the mechanism of action of these inhibitors, various novel styrylquinoline derivatives were synthesized and tested agains...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Zouhiri F,Mouscadet JF,Mekouar K,Desmaële D,Savouré D,Leh H,Subra F,Le Bret M,Auclair C,d'Angelo J

    更新日期:2000-04-20 00:00:00

  • Comparison of the reactivity of antimalarial 1,2,4,5-tetraoxanes with 1,2,4-trioxolanes in the presence of ferrous iron salts, heme, and ferrous iron salts/phosphatidylcholine.

    abstract::Dispiro-1,2,4,5-tetraoxanes and 1,2,4-trioxolanes represent attractive classes of synthetic antimalarial peroxides due to their structural simplicity, good stability, and impressive antimalarial activity. We investigated the reactivity of a series of potent amide functionalized tetraoxanes with Fe(II)gluconate, FeSO(4...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Bousejra-El Garah F,Wong MH,Amewu RK,Muangnoicharoen S,Maggs JL,Stigliani JL,Park BK,Chadwick J,Ward SA,O'Neill PM

    更新日期:2011-10-13 00:00:00

  • Synthesis and physicochemical, biological, and pharmacological properties of new bile acids amidated with cyclic amino acids.

    abstract::New analogs of cyclic amino acid-conjugated bile acids were synthesized, and their physicochemical and biological properties were compared with those of natural analogs. Ursodeoxycholic acid was amidated with D-proline, L-proline, 4-hydroxy-L-proline, and 4-methoxy-L-proline. Hyocholic and hyodeoxycholic acids were am...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Roda A,Cerrè C,Manetta AC,Cainelli G,Umani-Ronchi A,Panunzio M

    更新日期:1996-05-24 00:00:00

  • Discovery of IACS-9439, a Potent, Exquisitely Selective, and Orally Bioavailable Inhibitor of CSF1R.

    abstract::Tumor-associated macrophages (TAMs) have a significant presence in the tumor stroma across multiple human malignancies and are believed to be beneficial to tumor growth. Targeting CSF1R has been proposed as a potential therapy to reduce TAMs, especially the protumor, immune-suppressive M2 TAMs. Additionally, the high ...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Czako B,Marszalek JR,Burke JP,Mandal P,Leonard PG,Cross JB,Mseeh F,Jiang Y,Chang EQ,Suzuki E,Kovacs JJ,Feng N,Gera S,Harris AL,Liu Z,Mullinax RA,Pang J,Parker CA,Spencer ND,Yu SS,Wu Q,Tremblay MR,Mikule K,Wi

    更新日期:2020-09-10 00:00:00

  • Second-generation leukotriene B4 receptor antagonists related to SC-41930: heterocyclic replacement of the methyl ketone pharmacophore.

    abstract::Our previous reports have highlighted the first-generation leukotriene B4 (LTB4) receptor antagonist SC-41930 (7-[3-(4-acetyl-3-methoxy-2-propylphenoxy)propoxy]3,4- dihydro-8-propyl-2H-1-benzopyran-2-carboxylic acid) which has potent oral, topical, and intracolonic activity in various animal models of inflammation. Ex...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Penning TD,Djuric SW,Miyashiro JM,Yu S,Snyder JP,Spangler D,Anglin CP,Fretland DJ,Kachur JF,Keith RH

    更新日期:1995-03-17 00:00:00

  • Substituted trans-stilbenes, including analogues of the natural product resveratrol, inhibit the human tumor necrosis factor alpha-induced activation of transcription factor nuclear factor kappaB.

    abstract::The transcription factor nuclear factor kappaB (NF-kappaB), which regulates expression of numerous antiinflammatory genes as well as genes that promote development of the prosurvival, antiapoptotic state is up-regulated in many cancer cells. The natural product resveratrol, a polyphenolic trans-stilbene, has numerous ...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Heynekamp JJ,Weber WM,Hunsaker LA,Gonzales AM,Orlando RA,Deck LM,Jagt DL

    更新日期:2006-11-30 00:00:00

  • 5,6,7,8-Tetrahydro-1,6-naphthyridine Derivatives as Potent HIV-1-Integrase-Allosteric-Site Inhibitors.

    abstract::A series of 5,6,7,8-tetrahydro-1,6-naphthyridine derivatives targeting the allosteric lens-epithelium-derived-growth-factor-p75 (LEDGF/p75)-binding site on HIV-1 integrase, an attractive target for antiviral chemotherapy, was prepared and screened for activity against HIV-1 infection in cell culture. Small molecules t...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Peese KM,Allard CW,Connolly T,Johnson BL,Li C,Patel M,Sorensen ME,Walker MA,Meanwell NA,McAuliffe B,Minassian B,Krystal M,Parker DD,Lewis HA,Kish K,Zhang P,Nolte RT,Simmermacher J,Jenkins S,Cianci C,Naidu BN

    更新日期:2019-02-14 00:00:00

  • Synthetic mimics of antimicrobial peptides from triaryl scaffolds.

    abstract::In this report, we describe the synthesis of a new series of small amphiphilic aromatic compounds that mimic the essential properties of cationic antimicrobial peptides using Suzuki-Miyaura coupling. The new design allowed the easy tuning of the conformational restriction, controlled by introduction of intramolecular ...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Thaker HD,Sgolastra F,Clements D,Scott RW,Tew GN

    更新日期:2011-04-14 00:00:00

  • Structure-activity relationships in luteinizing hormone-releasing hormone.

    abstract::Three analogs of luteinizing hormone-releasing hormone (LH-RH) of the structure less than Glu-His-Trp-Ser-Tyr-Gly-Gly-Leu-Arg-Pro-Gly-NH2, involving substitutions inpositions 1, 3, and 8 with nonprotein amino acids, have been synthesized by the solid-phase method. They are [pyro-L-alpha-(1-aminoadipic)]-LH-RH, [3-(2-n...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Prasad KU,Roeske RW,Weitl FL,Vilchez-Martinez JA,Schally AV

    更新日期:1976-04-01 00:00:00

  • Preparation and analgesic activity of (-)-11 alpha-substituted 1,2,3,4,5,6-hexahydro-6 alpha,7-(methyleneoxy)-2,6-methano-3-benzazocines.

    abstract::Dihydrocodeinone oxime (1) under Beckmann rearrangement conditions gave a product (2) that facilitated the preparation of (-)-11 alpha-substituted 1,2,3,4,5,6-hexahydro-6 alpha,7-(methyleneoxy)-2,6-methano-3-benzazocines, a hitherto little-examined series of morphine partial structures. Compounds 7a and 12 gave good l...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Cittern PA,Kapoor VK,Parfitt RT

    更新日期:1986-10-01 00:00:00

  • Synthesis, conformation, and immunosuppressive activities of three analogues of cyclosporin A modified in the 1-position.

    abstract::The syntheses of three new cyclosporin A (CsA) analogues that contain novel MeBmt derivatives in the 1-position are described. The MeBmt analogue that contains an additional methyl group on C4, (2S,3R,6E)-4,4-dimethyl-3-hydroxy-2-(N-methylamino)-6-octenoic acid (MeBm2t), was synthesized in four steps beginning with th...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Aebi JD,Deyo DT,Sun CQ,Guillaume D,Dunlap B,Rich DH

    更新日期:1990-03-01 00:00:00

  • Development of melanoma-targeted polymer micelles by conjugation of a melanocortin 1 receptor (MC1R) specific ligand.

    abstract::The incidence of malignant melanoma is rising faster than that of any other cancer in the United States. Because of its high expression on the surface of melanomas, MC1R has been investigated as a target for selective imaging and therapeutic agents against melanoma. Eight ligands were screened against cell lines engin...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Barkey NM,Tafreshi NK,Josan JS,De Silva CR,Sill KN,Hruby VJ,Gillies RJ,Morse DL,Vagner J

    更新日期:2011-12-08 00:00:00

  • Synthesis of novel potent dipeptidyl peptidase IV inhibitors with enhanced chemical stability: interplay between the N-terminal amino acid alkyl side chain and the cyclopropyl group of alpha-aminoacyl-l-cis-4,5-methanoprolinenitrile-based inhibitors.

    abstract::A series of methanoprolinenitrile-containing dipeptide mimetics were synthesized and assayed as inhibitors of the N-terminal sequence-specific serine protease dipeptidyl peptidase IV (DPP-IV). The catalytic action of DPP-IV is the principle means of degradation of glucagon-like peptide-1, a key mediator of glucose-sti...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Magnin DR,Robl JA,Sulsky RB,Augeri DJ,Huang Y,Simpkins LM,Taunk PC,Betebenner DA,Robertson JG,Abboa-Offei BE,Wang A,Cap M,Xin L,Tao L,Sitkoff DF,Malley MF,Gougoutas JZ,Khanna A,Huang Q,Han SP,Parker RA,Hamann LG

    更新日期:2004-05-06 00:00:00

  • Discovery of Tetrahydroquinoxalines as Bromodomain and Extra-Terminal Domain (BET) Inhibitors with Selectivity for the Second Bromodomain.

    abstract::The bromodomain and extra-terminal domain (BET) family of proteins bind acetylated lysine residues on histone proteins. The four BET bromodomains-BRD2, BRD3, BRD4, and BRDT-each contain two bromodomain modules. BET bromodomain inhibition is a potential therapy for various cancers and immunoinflammatory diseases, but f...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Law RP,Atkinson SJ,Bamborough P,Chung CW,Demont EH,Gordon LJ,Lindon M,Prinjha RK,Watson AJB,Hirst DJ

    更新日期:2018-05-24 00:00:00

  • Prazosin-related compounds. Effect of transforming the piperazinylquinazoline moiety into an aminomethyltetrahydroacridine system on the affinity for alpha1-adrenoreceptors.

    abstract::In a search for structurally new alpha(1)-adrenoreceptor (alpha(1)-AR) antagonists, prazosin (1)-related compounds 2-11 were synthesized and their affinity profiles were assessed by functional experiments in isolated rat vas deferens (alpha(1A)), spleen (alpha(1B)), and aorta (alpha(1D)) and by binding assays in CHO c...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Rosini M,Antonello A,Cavalli A,Bolognesi ML,Minarini A,Marucci G,Poggesi E,Leonardi A,Melchiorre C

    更新日期:2003-11-06 00:00:00

  • Identification of G protein-coupled receptor 120-selective agonists derived from PPARgamma agonists.

    abstract::A weak, nonselective G protein-coupled receptor 120 (GPR120) agonist 10 was found by screening a series of carboxylic acids derived from the peroxisome proliferator-activated receptor gamma (PPARgamma) agonist 3. Modification based on the homology model of GPR120 led to the first GPR120-selective agonist 12. These res...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Suzuki T,Igari S,Hirasawa A,Hata M,Ishiguro M,Fujieda H,Itoh Y,Hirano T,Nakagawa H,Ogura M,Makishima M,Tsujimoto G,Miyata N

    更新日期:2008-12-11 00:00:00

  • Synthesis and pharmacological characterization of exo-2-(2'-chloro-5-pyridinyl)-7-(endo and exo)-aminobicyclo[2.2.1]heptanes as novel epibatidine analogues.

    abstract::Procedures were developed for the synthesis of exo-(2'-chloro-5-pyridinyl)-7-(endo and exo)-amino[2.2.1]heptanes (3a and 3b). The compounds were evaluated for binding to the alpha4beta2 and alpha7 nicotinic acetylcholine receptors (nAChRs), for pharmacological activity in the mouse tail-flick and hot-plate assays, and...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Carroll FI,Brieaddy LE,Navarro HA,Damaj MI,Martin BR

    更新日期:2005-11-17 00:00:00

  • Fluorescence-enhanced europium-diethylenetriaminepentaacetic (DTPA)-monoamide complexes for the assessment of renal function.

    abstract::Real-time, noninvasive assessment of glomerular filtration rate (GFR) is essential not only for monitoring critically ill patients at the bedside, but also for staging and monitoring patients with chronic kidney disease. In our pursuit to develop exogenous luminescent probes for dynamic optical monitoring of GFR, we h...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Chinen LK,Galen KP,Kuan KT,Dyszlewski ME,Ozaki H,Sawai H,Pandurangi RS,Jacobs FG,Dorshow RB,Rajagopalan R

    更新日期:2008-02-28 00:00:00

  • Novel Strategies To Activate the Dopamine D1 Receptor: Recent Advances in Orthosteric Agonism and Positive Allosteric Modulation.

    abstract::The five dopamine receptor subtypes (D1-5) are activated by the endogenous catecholamine dopamine. Sustained research has sought to identify selective ligands for receptor subtypes. In particular, activation of the D1 receptor has attracted attention due to its promising role in neurological diseases. Initial attempts...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章,评审


    authors: Hall A,Provins L,Valade A

    更新日期:2019-01-10 00:00:00

  • A nonionic inhibitor with high specificity for the UDP-Gal donor binding site of human blood group B galactosyltransferase: design, synthesis, and characterization.

    abstract::9-(5-O-α-D-galactopyranosyl)-D-arabinityl-1,3,7-trihydropurine-2,6,8-trione (1) was designed and synthesized as a nonionic inhibitor for the donor binding site of human blood group B galactosyltransferase (GTB). Enzymatic characterization showed 1 to be extremely specific, as the highly homologous human N-acetylgalact...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Schaefer K,Sindhuwinata N,Hackl T,Kötzler MP,Niemeyer FC,Palcic MM,Peters T,Meyer B

    更新日期:2013-03-14 00:00:00

  • Antibacterial inhibitors of Gram-positive thymidylate kinase: structure-activity relationships and chiral preference of a new hydrophobic binding region.

    abstract::Thymidylate kinase (TMK), an essential enzyme in bacterial DNA biosynthesis, is an attractive therapeutic target for the development of novel antibacterial agents, and we continue to explore TMK inhibitors with improved potency, protein binding, and pharmacokinetic potential. A structure-guided design approach was emp...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Kawatkar SP,Keating TA,Olivier NB,Breen JN,Green OM,Guler SY,Hentemann MF,Loch JT,McKenzie AR,Newman JV,Otterson LG,Martínez-Botella G

    更新日期:2014-06-12 00:00:00

  • Conformational analysis of dopamine D-2 receptor antagonists of the benzamide series in relation to a recently proposed D-2 receptor-interaction model.

    abstract::Conformational analysis using molecular mechanics calculations (MM2(87)) has been performed for four different types of benzamides which display high affinity for the dopamine D-2 receptor. In order to elucidate the conformation of the receptor-bound molecules, a previously described dopamine D-2 receptor-interaction ...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Pettersson I,Liljefors T

    更新日期:1992-06-26 00:00:00

  • Structure-Based Optimization of Nonquaternary Reactivators of Acetylcholinesterase Inhibited by Organophosphorus Nerve Agents.

    abstract::Acetylcholinesterase (AChE), a key enzyme in the central and peripheral nervous systems, is the principal target of organophosphorus nerve agents. Quaternary oximes can regenerate AChE activity by displacing the phosphyl group of the nerve agent from the active site, but they are poorly distributed in the central nerv...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Santoni G,de Sousa J,de la Mora E,Dias J,Jean L,Sussman JL,Silman I,Renard PY,Brown RCD,Weik M,Baati R,Nachon F

    更新日期:2018-09-13 00:00:00