Novel N-Substituted Benzomorphan-Based Compounds: From MOR-Agonist/DOR-Antagonist to Biased/Unbiased MOR Agonists.

Abstract:

:Modifications at the basic nitrogen of the benzomorphan scaffold allowed the development of compounds able to segregate physiological responses downstream of the receptor signaling, opening new possibilities in opioid drug development. Alkylation of the phenyl ring in the N-substituent of the MOR-agonist/DOR-antagonist LP1 resulted in retention of MOR affinity. Moreover, derivatives 7a, 7c, and 7d were biased MOR agonists toward ERK1,2 activity stimulation, whereas derivative 7e was a low potency MOR agonist on adenylate cyclase inhibition. They were further screened in the mouse tail flick test and PGE2-induced hyperalgesia and drug-induced gastrointestinal transit.

journal_name

ACS Med Chem Lett

authors

Pasquinucci L,Parenti C,Ruiz-Cantero MC,Georgoussi Z,Pallaki P,Cobos EJ,Amata E,Marrazzo A,Prezzavento O,Arena E,Dichiara M,Salerno L,Turnaturi R

doi

10.1021/acsmedchemlett.9b00549

subject

Has Abstract

pub_date

2020-01-28 00:00:00

pages

678-685

issue

5

issn

1948-5875

journal_volume

11

pub_type

杂志文章
  • Exploring Halogen Bonds in 5-Hydroxytryptamine 2B Receptor-Ligand Interactions.

    abstract::Here, we predicted the potential halogen bonding interaction between compound 2 and the 5-hydroxytryptamine 2B (5-HT2B) receptor and systematically assessed this interaction via structure-activity relationship analysis and molecular dynamics simulations. A physics-based computational protocol was then developed to fur...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1021/acsmedchemlett.8b00300

    authors: Zhou Y,Wang Y,Li P,Huang XP,Qi X,Du Y,Huang N

    更新日期:2018-10-01 00:00:00

  • Design, Synthesis, and Characterization of a Fluorescence Polarization Pan-BET Bromodomain Probe.

    abstract::Several chemical probes have been developed for use in fluorescence polarization screening assays to aid in drug discovery for the bromodomain and extra-terminal domain (BET) proteins. However, few of those have been characterized in the literature. We have designed, synthesized, and thoroughly characterized a novel f...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1021/acsmedchemlett.8b00380

    authors: Paulson CN,Guan X,Ayoub AM,Chan A,Karim RM,Pomerantz WCK,Schönbrunn E,Georg GI,Hawkinson JE

    更新日期:2018-10-31 00:00:00

  • Structure-Based Virtual Screening for the Discovery of Novel Inhibitors of New Delhi Metallo-β-lactamase-1.

    abstract::Bacterial resistance has become a worldwide concern after the emergence of metallo-β-lactamases (MBLs). They represent one of the major mechanisms of bacterial resistance against beta-lactam antibiotics. Among MBLs, New Delhi metallo-β-lactamase-1 NDM-1, the most prevalent type, is extremely efficient in inactivating ...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1021/acsmedchemlett.7b00428

    authors: Spyrakis F,Celenza G,Marcoccia F,Santucci M,Cross S,Bellio P,Cendron L,Perilli M,Tondi D

    更新日期:2017-11-26 00:00:00

  • Enhanced Cytotoxicity through Conjugation of a "Clickable" Luminescent Re(I) Complex to a Cell-Penetrating Lipopeptide.

    abstract::Re(I) tricarbonyl polypyridine-based complexes are particularly attractive metal complexes in the field of inorganic chemical biology due to their luminescent properties, ease of conjugation to targeting biomolecules, and the possibility to prepare their "hot" (99m)Tc analogues for radioimaging. In this study, we prep...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1021/ml500158w

    authors: Leonidova A,Pierroz V,Adams LA,Barlow N,Ferrari S,Graham B,Gasser G

    更新日期:2014-05-15 00:00:00

  • Discovery of Bivalent Kinase Inhibitors via Enzyme-Templated Fragment Elaboration.

    abstract::We have employed novel fragment-based screening methodology to discover bivalent kinase inhibitors with improved selectivity. Starting from a low molecular weight promiscuous kinase inhibitor, we appended a thiol for subsequent reaction with a library of acrylamide electrophiles. Enzyme-templated screening was perform...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1021/acsmedchemlett.5b00167

    authors: Kwarcinski FE,Steffey ME,Fox CC,Soellner MB

    更新日期:2015-07-13 00:00:00

  • The Dark Side of Fluorine.

    abstract::Despite the perceived stability of the C-F bond, chemical instability and drug-metabolizing enzymes can lead to its cleavage. The resulting release of fluoride and formation of certain metabolites may cause safety issues and warrant the medicinal chemists' attention. ...

    journal_title:ACS medicinal chemistry letters

    pub_type: 社论

    doi:10.1021/acsmedchemlett.9b00235

    authors: Pan Y

    更新日期:2019-06-20 00:00:00

  • Discovery of AG-120 (Ivosidenib): A First-in-Class Mutant IDH1 Inhibitor for the Treatment of IDH1 Mutant Cancers.

    abstract::Somatic point mutations at a key arginine residue (R132) within the active site of the metabolic enzyme isocitrate dehydrogenase 1 (IDH1) confer a novel gain of function in cancer cells, resulting in the production of d-2-hydroxyglutarate (2-HG), an oncometabolite. Elevated 2-HG levels are implicated in epigenetic alt...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1021/acsmedchemlett.7b00421

    authors: Popovici-Muller J,Lemieux RM,Artin E,Saunders JO,Salituro FG,Travins J,Cianchetta G,Cai Z,Zhou D,Cui D,Chen P,Straley K,Tobin E,Wang F,David MD,Penard-Lacronique V,Quivoron C,Saada V,de Botton S,Gross S,Dang L,Y

    更新日期:2018-01-19 00:00:00

  • Tariquidar-Related Chalcones and Ketones as ABCG2 Modulators.

    abstract::ABC transporters, including ABCG2, play a vital role in defending the human body against the vast range of xenobiotics. Even though this is beneficial for human health, these protein transporters have been implicated in the emerging resistance of cancer cells to a variety of structurally and functionally diverse antic...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1021/acsmedchemlett.8b00289

    authors: Peña-Solórzano D,Scholler M,Bernhardt G,Buschauer A,König B,Ochoa-Puentes C

    更新日期:2018-07-25 00:00:00

  • Triazole Appending Agent (TAAG): A New Synthon for Preparing Iodine-Based Molecular Imaging and Radiotherapy Agents.

    abstract::A new prosthetic group referred to as the triazole appending agent (TAAG) was developed as a means to prepare targeted radioiodine-based molecular imaging and therapy agents. Tributyltin-TAAG and the fluorous analogue were synthesized in high yield using simple click chemistry and the products labeled in greater than ...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1021/ml300003v

    authors: Darwish A,Blacker M,Janzen N,Rathmann SM,Czorny S,Hillier SM,Joyal JL,Babich JW,Valliant JF

    更新日期:2012-02-18 00:00:00

  • Minibody-indocyanine green based activatable optical imaging probes: the role of short polyethylene glycol linkers.

    abstract::Minibodies show rapider blood clearance than IgGs due to smaller size that improves target-to-background ratio (TBR) in in vivo imaging. Additionally, the ability to activate an optical probe after binding to the target greatly improves the TBR. An optical imaging probe based on a minibody against prostate-specific me...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1021/ml400533y

    authors: Watanabe R,Sato K,Hanaoka H,Harada T,Nakajima T,Kim I,Paik CH,Wu AM,Choyke PL,Kobayashi H

    更新日期:2014-01-17 00:00:00

  • Discovery and Optimization of Macrocyclic Quinoxaline-pyrrolo-dihydropiperidinones as Potent Pim-1/2 Kinase Inhibitors.

    abstract::The identification of Pim-1/2 kinase overexpression in B-cell malignancies suggests that Pim kinase inhibitors will have utility in the treatment of lymphoma, leukemia, and multiple myeloma. Starting from a moderately potent quinoxaline-dihydropyrrolopiperidinone lead, we recognized the potential for macrocyclization ...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1021/acsmedchemlett.5b00403

    authors: Cee VJ,Chavez F Jr,Herberich B,Lanman BA,Pettus LH,Reed AB,Wu B,Wurz RP,Andrews KL,Chen J,Hickman D,Laszlo J 3rd,Lee MR,Guerrero N,Mattson BK,Nguyen Y,Mohr C,Rex K,Sastri CE,Wang P,Wu Q,Wu T,Xu Y,Zhou Y,Wi

    更新日期:2016-02-12 00:00:00

  • Discovery of CDK5 Inhibitors through Structure-Guided Approach.

    abstract::Specific abrogation of cyclin-dependent kinase 5 (CDK5) activity has been validated as a viable approach for the development of anticancer agents. However, no selective CDK5 inhibitor has been reported to date. Herein, a structure-based in silico screening was employed to identify novel scaffolds from a library of com...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1021/acsmedchemlett.9b00029

    authors: Khair NZ,Lenjisa JL,Tadesse S,Kumarasiri M,Basnet SKC,Mekonnen LB,Li M,Diab S,Sykes MJ,Albrecht H,Milne R,Wang S

    更新日期:2019-03-20 00:00:00

  • Thiophene-Pyrazolourea Derivatives as Potent, Orally Bioavailable, and Isoform-Selective JNK3 Inhibitors.

    abstract::Potent JNK3 isoform selective inhibitors were developed from a thiophenyl-pyrazolourea scaffold. Through structure activity relationship (SAR) studies utilizing enzymatic and cell-based assays, and in vitro and in vivo drug metabolism and pharmacokinetic (DMPK) studies, potent and highly selective JNK3 inhibitors with...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1021/acsmedchemlett.0c00533

    authors: Feng Y,Park H,Bauer L,Ryu JC,Yoon SO

    更新日期:2020-12-13 00:00:00

  • JAK2 JH2 Fluorescence Polarization Assay and Crystal Structures for Complexes with Three Small Molecules.

    abstract::A competitive fluorescence polarization (FP) assay is reported for determining binding affinities of probe molecules with the pseudokinase JAK2 JH2 allosteric site. The syntheses of the fluorescent 5 and 6 used in the assay are reported as well as Kd results for 10 compounds, including JNJ7706621, NVP-BSK805, and filg...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1021/acsmedchemlett.7b00154

    authors: Newton AS,Deiana L,Puleo DE,Cisneros JA,Cutrona KJ,Schlessinger J,Jorgensen WL

    更新日期:2017-05-17 00:00:00

  • Multiple in Vitro Inhibition of HIV-1 Proteins by 2,6-Dipeptidyl-anthraquinone Conjugates Targeting the PBS RNA.

    abstract::We recently reported a series of 2,6-dipeptidyl-anthraquinone conjugates (AQs) as Trans-Activation Response element (TAR) RNA-binding agents able to inhibit in vitro the HIV-1 nucleocapsid (NC) protein-mediated processes. Because NC is a highly adaptable nucleic acid chaperone assisting several crucial steps along rev...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1021/acsmedchemlett.9b00682

    authors: Gamba E,Sosic A,Saccone I,Magli E,Frecentese F,Gatto B

    更新日期:2020-03-23 00:00:00

  • Effects of C-Terminal B-Chain Modifications in a Relaxin 3 Agonist Analogue.

    abstract::The receptor for the neuropeptide relaxin 3, relaxin family peptide 3 (RXFP3) receptor, is an attractive pharmacological target for the control of eating, addictive, and psychiatric behaviors. Several structure-activity relationship studies on both human relaxin 3 (containing 3 disulfide bonds) and its analogue A2 (tw...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1021/acsmedchemlett.0c00456

    authors: Praveen P,Tailhades J,Rosengren KJ,Liu M,Wade JD,Bathgate RAD,Hossain MA

    更新日期:2020-10-22 00:00:00

  • Discovery of Membrane-Bound Pyrophosphatase Inhibitors Derived from an Isoxazole Fragment.

    abstract::Membrane-bound pyrophosphatases (mPPases) regulate energy homeostasis in pathogenic protozoan parasites and lack human homologues, which makes them promising targets in e.g. malaria. Yet only few nonphosphorus inhibitors have been reported so far. Here, we explore an isoxazole fragment hit, leading to the discovery of...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1021/acsmedchemlett.9b00537

    authors: Johansson NG,Turku A,Vidilaseris K,Dreano L,Khattab A,Ayuso Pérez D,Wilkinson A,Zhang Y,Tamminen M,Grazhdankin E,Kiriazis A,Fishwick CWG,Meri S,Yli-Kauhaluoma J,Goldman A,Boije Af Gennäs G,Xhaard H

    更新日期:2020-02-17 00:00:00

  • Design and Optimization of Benzopiperazines as Potent Inhibitors of BET Bromodomains.

    abstract::A protein structure-guided drug design approach was employed to develop small molecule inhibitors of the BET family of bromodomains that were distinct from the known (+)-JQ1 scaffold class. These efforts led to the identification of a series of substituted benzopiperazines with structural features that enable interact...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1021/acsmedchemlett.7b00191

    authors: Millan DS,Kayser-Bricker KJ,Martin MW,Talbot AC,Schiller SER,Herbertz T,Williams GL,Luke GP,Hubbs S,Alvarez Morales MA,Cardillo D,Troccolo P,Mendes RL,McKinnon C

    更新日期:2017-07-14 00:00:00

  • Enhancing a CH-π Interaction to Increase the Affinity for 5-HT1A Receptors.

    abstract::An electrostatic interaction related to a favorable position of the distal phenyl ring and a phenylalanine residue in the binding pocket would explain the higher 5-HT1A affinity of a 4-phenyl-1,2,3,6-tetrahydropyridine (THP) analogue compared to the corresponding 4-phenylpiperazine analogue. To explore a possible rein...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1021/ml4004843

    authors: Liégeois JF,Lespagnard M,Meneses Salas E,Mangin F,Scuvée-Moreau J,Dilly S

    更新日期:2014-01-29 00:00:00

  • Structure-Metabolism Relationships in the Glucuronidation of d-Amino Acid Oxidase Inhibitors.

    abstract::Representative d-amino acid oxidase (DAAO) inhibitors were subjected to in vitro liver microsomal stability tests in the absence or presence of uridine diphosphate glucuronic acid (UDPGA). While carboxylate-based DAAO inhibitors displayed little glucuronidation, most DAAO inhibitors containing α-hydroxycarbonyl moiety...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1021/ml500335z

    authors: Zimmermann SC,Rais R,Alt J,Burzynski C,Slusher BS,Tsukamoto T

    更新日期:2014-10-21 00:00:00

  • Structure-Guided Optimization of Replication Protein A (RPA)-DNA Interaction Inhibitors.

    abstract::Replication protein A (RPA) is the major human single stranded DNA (ssDNA)-binding protein, playing essential roles in DNA replication, repair, recombination, and DNA-damage response (DDR). Inhibition of RPA-DNA interactions represents a therapeutic strategy for cancer drug discovery and has great potential to provide...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1021/acsmedchemlett.9b00440

    authors: Gavande NS,VanderVere-Carozza PS,Pawelczak KS,Vernon TL,Jordan MR,Turchi JJ

    更新日期:2020-01-02 00:00:00

  • B-973, a Novel α7 nAChR Ago-PAM: Racemic and Asymmetric Synthesis, Electrophysiological Studies, and in Vivo Evaluation.

    abstract::We report here the total synthesis of B-973 (five steps), a recently identified α7 nAChR ago-PAM, its enantiomeric resolution, and its electrophysiological characterization in Xenopus oocytes to identify (-)-B-973B as the bioactive enantiomer. The asymmetric synthesis of B-973B was accomplished in 99% ee, and X-ray cr...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1021/acsmedchemlett.8b00407

    authors: Garai S,Raja KS,Papke RL,Deschamps JR,Damaj MI,Thakur GA

    更新日期:2018-10-11 00:00:00

  • Design, Synthesis, and Preclinical Characterization of the Selective Androgen Receptor Modulator (SARM) RAD140.

    abstract::This report describes the discovery of RAD140, a potent, orally bioavailable, nonsteroidal selective androgen receptor modulator (SARM). The characterization of RAD140 in several preclinical models of anabolic androgen action is also described. ...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1021/ml1002508

    authors: Miller CP,Shomali M,Lyttle CR,O'Dea LS,Herendeen H,Gallacher K,Paquin D,Compton DR,Sahoo B,Kerrigan SA,Burge MS,Nickels M,Green JL,Katzenellenbogen JA,Tchesnokov A,Hattersley G

    更新日期:2010-12-02 00:00:00

  • Structural Approach to Assessing the Innovativeness of New Drugs Finds Accelerating Rate of Innovation.

    abstract::Measuring innovation in the pharmaceutical industry is challenging. Counts of new molecular entities (NMEs) approved by the Food and Drug Administration (FDA) are commonly used, but this measure only gauges quantity not innovativeness. A new indicator of innovation for small molecule and peptide drugs based on structu...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1021/acsmedchemlett.0c00319

    authors: Wills TJ,Lipkus AH

    更新日期:2020-09-10 00:00:00

  • Characterizing the Covalent Targets of a Small Molecule Inhibitor of the Lysine Acetyltransferase P300.

    abstract::C646 inhibits the lysine acetyltransferases (KATs) p300 and CBP and represents the most potent and selective small molecule KAT inhibitor identified to date. To gain insights into the cellular activity of this epigenetic probe, we applied chemoproteomics to identify covalent targets of the C646 chemotype. Modeling and...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1021/acsmedchemlett.5b00385

    authors: Shrimp JH,Sorum AW,Garlick JM,Guasch L,Nicklaus MC,Meier JL

    更新日期:2015-10-31 00:00:00

  • The impact of ionization States of matrix metalloproteinase inhibitors on docking-based inhibitor design.

    abstract::The influence of ionization states of hydroxamates and retrohydroxamates and the presence of zinc ions in the active site were investigated using the wild-type and E402Q mutant of MMP-9. The deprotonated hydroxamates showed a significantly enhanced enrichment factor in the presence of zinc ions. A pharmacophore model ...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1021/ml200031m

    authors: Zhong H,Wees MA,Faure TD,Carrillo C,Arbiser J,Bowen JP

    更新日期:2011-03-29 00:00:00

  • Kinetic profile of amyloid formation in the presence of an aromatic inhibitor by nuclear magnetic resonance.

    abstract::The self-assembly of amyloid proteins into β-sheet rich assemblies is associated with human amyloidoses including Alzheimer's disease, Parkinson's disease, and type 2 diabetes. An attractive therapeutic strategy therefore is to develop small molecules that would inhibit protein self-assembly. Natural polyphenols are p...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1021/ml300147m

    authors: Liu G,Gaines JC,Robbins KJ,Lazo ND

    更新日期:2012-08-28 00:00:00

  • Discovery of Potent and Simplified Piperidinone-Based Inhibitors of the MDM2-p53 Interaction.

    abstract::Continued optimization of the N-substituent in the piperidinone series provided potent piperidinone-pyridine inhibitors 6, 7, 14, and 15 with improved pharmacokinetic properties in rats. Reducing structure complexity of the N-alkyl substituent led to the discovery of 23, a potent and simplified inhibitor of MDM2. Comp...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1021/ml500142b

    authors: Yu M,Wang Y,Zhu J,Bartberger MD,Canon J,Chen A,Chow D,Eksterowicz J,Fox B,Fu J,Gribble M,Huang X,Li Z,Liu JJ,Lo MC,McMinn D,Oliner JD,Osgood T,Rew Y,Saiki AY,Shaffer P,Yan X,Ye Q,Yu D,Zhao X,Zhou J,Ols

    更新日期:2014-06-30 00:00:00

  • Synthesis and antimalarial activity of 3,3-spiroanellated 5,6-disubstituted 1,2,4-trioxanes.

    abstract::Novel 3,3-spiroanellated 5-aryl, 6-arylvinyl-substituted 1,2,4-trioxanes 19-34 have been synthesized and appraised for their antimalarial activity against multidrug-resistant Plasmodium yoelii nigeriensis in Swiss mice by oral route at doses ranging from 96 mg/kg × 4 days to 24 mg/kg × 4 days. The most active compound...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1021/ml300188t

    authors: Maurya R,Soni A,Anand D,Ravi M,Raju KS,Taneja I,Naikade NK,Puri SK,Wahajuddin,Kanojiya S,Yadav PP

    更新日期:2012-12-11 00:00:00

  • Synthesis, Biological Evaluation, and Autophagy Mechanism of 12N-Substituted Sophoridinamines as Novel Anticancer Agents.

    abstract::A series of 12N-substituted sophoridinamine derivatives were synthesized and evaluated for their cytotoxic activities in human HepG2 hepatoma cells. Structure-activity relationship revealed that introduction of a suitable arylidene or arylethyl at the N'-end could greatly enhance antiproliferation potency. Among them,...

    journal_title:ACS medicinal chemistry letters

    pub_type: 杂志文章

    doi:10.1021/acsmedchemlett.6b00466

    authors: Bi C,Zhang N,Yang P,Ye C,Wang Y,Fan T,Shao R,Deng H,Song D

    更新日期:2017-01-05 00:00:00