Development of a bioavailable μ opioid receptor (MOPr) agonist, δ opioid receptor (DOPr) antagonist peptide that evokes antinociception without development of acute tolerance.


:We have previously described a cyclic tetrapeptide, 1, that displays μ opioid receptor (MOPr) agonist and δ opioid receptor (DOPr) antagonist activity, a profile associated with a reduced incidence of opioid tolerance and dependence. Like many peptides, 1 has poor bioavailability. We describe here an analogue of 1 with an added C-terminal β-glucosylserine residue, Ser(β-Glc)NH2, a modification that has previously been shown to improve bioavailability of opioid peptides. The resulting peptide, 4, exhibits full antinociceptive efficacy in the mouse warm water tail withdrawal assay after intraperitoneal administration with potency similar to that of morphine. Further, 4 does not give rise to acute tolerance and thus represents a promising lead for the development of opioid analgesics with reduced side effects.


J Med Chem


Mosberg HI,Yeomans L,Anand JP,Porter V,Sobczyk-Kojiro K,Traynor JR,Jutkiewicz EM




Has Abstract


2014-04-10 00:00:00












  • Inhibitors of hepatic mixed function oxidase. 3. Inhibition of hepatic microsomal aniline hydroxylase and aminopyrine demethylase by 2,6- and 2,4-dihydroxyphenyl alkyl ketones and related compounds.

    abstract::A series of 2,6- and 2,4-dihydroxyphenyl alkyl ketones has been investigated as inhibitors of hepatic microsomal aniline hydroxylase and aminopyrine demethylase activities. Structural alterations in both series did little to enhance the inhibitory activity of the parent compounds 2,6-dihydroxyacetophenone (3) and 2,4-...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Bobik A,Holder GM,Ryan AJ

    更新日期:1977-09-01 00:00:00

  • Novel KCNQ2/Q3 agonists as potential therapeutics for epilepsy and neuropathic pain.

    abstract::Current drugs for the treatment of seizure disorders, although effective in many patients, still suffer from a number of failures and are not effective in some forms of resistant epilepsies. Historically, many of these drugs have multiple mechanisms of action including calcium and sodium channel blockade as well as GA...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Fritch PC,McNaughton-Smith G,Amato GS,Burns JF,Eargle CW,Roeloffs R,Harrison W,Jones L,Wickenden AD

    更新日期:2010-01-28 00:00:00

  • Estrogenic potential of 2-alkyl-4-(thio)chromenone 6-O-sulfamates: potent inhibitors of human steroid sulfatase.

    abstract::2-Alkylchromen-4-one 6-O-sulfamates, a new class of potent steroid sulfatase (STS) inhibitors, were evaluated for their estrogenic potential. Structure-activity relationships for estrogenic activity were identified; however, no correlation with STS inhibition was found. Estrogenicity is favored by bulky side chains an...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Nussbaumer P,Winiski AP,Billich A

    更新日期:2003-11-06 00:00:00

  • Chemically stable N-methyl-4-(alkylthio)cyclophosphamide derivatives as prodrugs of 4-hydroxycyclophosphamide.

    abstract::Two prototype N-methyl-4-thio-substituted cyclophosphamide (CP) derivatives (5 and 6), prodrugs of 4-hydroxycyclophosphamide (4-HO-CP), were designed to undergo oxidative N-demethylation to release the active alkylating agent. These prodrugs were chemically stable until oxidatively N-demethylated in the presence of he...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Moon KY,Shirota FN,Baturay N,Kwon CH

    更新日期:1995-03-03 00:00:00

  • Chemistry and pharmacology of the non-benzodiazepine anxiolytic enciprazine and related compounds.

    abstract::In the course of studies on tranquilizers, new non-benzodiazepine-like compounds were synthesized. These are 1-(3,4,5-trimethoxyphenoxy)-3-[4-(2-methoxyphenyl)piperazinyl]prop an-2-ol (INN: enciprazine) and derivatives thereof which were screened pharmacologically in order to evaluate their central nervous system acti...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Engel J,Fleischhauer I,Jakovlev V,Kleemann A,Kutscher B,Nickel B,Rauer H,Werner U,Szelenyi I,Johanson CE

    更新日期:1990-11-01 00:00:00

  • Spirocyclopropyl beta-lactams as mechanism-based inhibitors of serine beta-lactamases. Synthesis by rhodium-catalyzed cyclopropanation of 6-diazopenicillanate sulfone.

    abstract::Class A-class C mechanism-based beta-lactamase inhibitors were designed on the basis of the intermediacy of an oxycarbenium species capable of cross-linking with amino acids residues in the active site. Penams 24 and 27 were very potent against AmpC in vitro. The MIC values of 24 in combination with piperacillin again...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Sandanayaka VP,Prashad AS,Yang Y,Williamson RT,Lin YI,Mansour TS

    更新日期:2003-06-19 00:00:00

  • Potent inhibition of Grb2 SH2 domain binding by non-phosphate-containing ligands.

    abstract::Development of Grb2 Src homology 2 (SH2) domain binding inhibitors has important implications for treatment of a variety of diseases, including several cancers. In cellular studies, inhibitors of Grb2 SH2 domain binding have to date been large, highly charged peptides which relied on special transport devices for cell...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Yao ZJ,King CR,Cao T,Kelley J,Milne GW,Voigt JH,Burke TR Jr

    更新日期:1999-01-14 00:00:00

  • Synthesis and antineoplastic properties of ether-linked thioglycolipids.

    abstract::Ether-linked glycero-alpha- and beta-D-glucopyranosides and glycero-1-thio-alpha- and beta-D-glucopyranosides have been synthesized by modifications of the Königs-Knorr procedure, and their antitumor activities have been evaluated. The bioactivities of these compounds have been evaluated in five different cell lines (...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Guivisdalsky PN,Bittman R,Smith Z,Blank ML,Snyder F,Howard S,Salari H

    更新日期:1990-09-01 00:00:00

  • Cytotoxicity of cis-platinum(II) conjugate models. The effect of chelating arms and leaving groups on cytotoxicity: a quantitative structure-activity relationship approach.

    abstract::Thirteen newly synthesized or resynthesized diamine-platinum(II) complexes were characterized, and their cytotoxic activities (IC50) were tested on parental and resistant ovarian cancer cell lines. They represent models of conjugates between biologically active vectors and cytotoxic Pt(II) moieties within the "drug ta...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Monti E,Gariboldi M,Maiocchi A,Marengo E,Cassino C,Gabano E,Osella D

    更新日期:2005-02-10 00:00:00

  • An interdisciplinary approach to the design of new structures active at the beta-adrenergic receptor. Aliphatic oxime ether derivatives.

    abstract::On the basis of results previously obtained from structural and theoretical studies on beta-adrenergic drugs, a series of aliphatic oxime ether derivatives (AOEDs) was synthesized. As expected, pharmacological in vitro tests showed that compounds examined exhibit a marked and competitive antagonism at beta-adrenocepto...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Macchia B,Balsamo A,Lapucci A,Martinelli A,Macchia F,Breschi MC,Fantoni B,Martinotti E

    更新日期:1985-02-01 00:00:00

  • Structural optimization affording 2-(R)-(1-(R)-3, 5-bis(trifluoromethyl)phenylethoxy)-3-(S)-(4-fluoro)phenyl-4- (3-oxo-1,2,4-triazol-5-yl)methylmorpholine, a potent, orally active, long-acting morpholine acetal human NK-1 receptor antagonist.

    abstract::Structural modifications requiring novel synthetic chemistry were made to the morpholine acetal human neurokinin-1 (hNK-1) receptor antagonist 4, and this resulted in the discovery of 2-(R)-(1-(R)-3, 5-bis(trifluoromethyl)phenylethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-ox o-1 ,2,4-triazol-5-yl)methyl morpholine (17). This m...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Hale JJ,Mills SG,MacCoss M,Finke PE,Cascieri MA,Sadowski S,Ber E,Chicchi GG,Kurtz M,Metzger J,Eiermann G,Tsou NN,Tattersall FD,Rupniak NM,Williams AR,Rycroft W,Hargreaves R,MacIntyre DE

    更新日期:1998-11-05 00:00:00

  • Structure-activity relationships of analogues of thapsigargin modified at O-11 and O-12.

    abstract::A number of analogues of thapsigargin have been synthesized by alkylating or acylating O-11 and O-12 in the lactol obtained by reducing thapsigargicin. Introduction of alpha-disposed substituents decreased the Ca(2+)-ATPase inhibitory potency of the analogue, whereas the enzyme was more tolerant toward beta-disposed s...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Nielsen SF,Thastrup O,Pedersen R,Olsen CE,Christensen SB

    更新日期:1995-01-20 00:00:00

  • Synthesis and antiviral activity of 4-benzyl pyridinone derivatives as potent and selective non-nucleoside human immunodeficiency virus type 1 reverse transcriptase inhibitors.

    abstract::Several 4-benzyl analogues of 5-ethyl-6-methyl-4-(phenylthio)pyridin-2(1H)-ones were synthesized and evaluated for their anti-HIV-l activities. Key transformations include metalation at the 4-C-position of 5-ethyl-2-methoxy-6-methyl-3-pivaloylaminopyridine (5) and its coupling with benzyl bromide or benzaldehyde deriv...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Dollé V,Nguyen CH,Legraverend M,Aubertin AM,Kirn A,Andreola ML,Ventura M,Tarrago-Litvak L,Bisagni E

    更新日期:2000-10-19 00:00:00

  • Studies on some derivatives of oxamniquine.

    abstract::On the basis of the remarkable biological similarities between hycanthone and oxamniquine and as a sequel to our finding that some esters of hycanthone are active against hycanthone-resistant schistosomes, we prepared oxamniquine acetate, oxamniquine N-methylcarbamate, and four substituted phenylsulfonohydrazones of o...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: el-Hamouly W,Pica-Mattoccia L,Cioli D,Schwartz HM,Archer S

    更新日期:1988-08-01 00:00:00

  • Jatrophane diterpenes as modulators of multidrug resistance. Advances of structure-activity relationships and discovery of the potent lead pepluanin A.

    abstract::From the whole plant of Euphorbia peplus L., five new diterpenes based on a jatrophane skeleton (pepluanins A-E, 1-5) were isolated, together with two known analogues (6 and 7), which served to divulge in detail the structure-activity relationships within this class of P-glycoprotein inhibitors. The results revealed t...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Corea G,Fattorusso E,Lanzotti V,Motti R,Simon PN,Dumontet C,Di Pietro A

    更新日期:2004-02-12 00:00:00

  • Structure-based design, synthesis, and antimicrobial activity of indazole-derived SAH/MTA nucleosidase inhibitors.

    abstract::The structure-based design, synthesis, and biological activity of a novel indazole-containing inhibitor series for S-adenosyl homocysteine/methylthioadenosine (SAH/MTA) nucleosidase are described. Use of 5-aminoindazole as the core scaffold provided a structure-guided series of low nanomolar inhibitors with broad-spec...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Li X,Chu S,Feher VA,Khalili M,Nie Z,Margosiak S,Nikulin V,Levin J,Sprankle KG,Tedder ME,Almassy R,Appelt K,Yager KM

    更新日期:2003-12-18 00:00:00

  • New series of morpholine and 1,4-oxazepane derivatives as dopamine D4 receptor ligands: synthesis and 3D-QSAR model.

    abstract::Since the identification of the dopamine D(4) receptor subtype and speculations about its possible involvement in schizophrenia, much work has been put into development of selective D(4) ligands. These selective ligands may be effective antipsychotics without extrapyramidal side effects. This work describes the synthe...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Audouze K,Nielsen EØ,Peters D

    更新日期:2004-06-03 00:00:00

  • A copper(I)-catalyzed 1,2,3-triazole azide-alkyne click compound is a potent inhibitor of a multidrug-resistant HIV-1 protease variant.

    abstract::Treatment with HIV-1 protease inhibitors, a component of highly active antiretroviral therapy (HAART), often results in viral resistance. Structural and biochemical characterization of a 6X protease mutant arising from in vitro selection with compound 1, a C 2-symmetric diol protease inhibitor, has been previously des...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Giffin MJ,Heaslet H,Brik A,Lin YC,Cauvi G,Wong CH,McRee DE,Elder JH,Stout CD,Torbett BE

    更新日期:2008-10-23 00:00:00

  • Discovery of danoprevir (ITMN-191/R7227), a highly selective and potent inhibitor of hepatitis C virus (HCV) NS3/4A protease.

    abstract::HCV serine protease NS3 represents an attractive drug target because it is not only essential for viral replication but also implicated in the viral evasion of the host immune response pathway through direct cleavage of key proteins in the human innate immune system. Through structure-based drug design and optimizatio...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Jiang Y,Andrews SW,Condroski KR,Buckman B,Serebryany V,Wenglowsky S,Kennedy AL,Madduru MR,Wang B,Lyon M,Doherty GA,Woodard BT,Lemieux C,Geck Do M,Zhang H,Ballard J,Vigers G,Brandhuber BJ,Stengel P,Josey JA,Beigelm

    更新日期:2014-03-13 00:00:00

  • Structure-guided design of A(3) adenosine receptor-selective nucleosides: combination of 2-arylethynyl and bicyclo[3.1.0]hexane substitutions.

    abstract::(N)-Methanocarba adenosine 5'-methyluronamides containing known A(3) AR (adenosine receptor)-enhancing modifications, i.e., 2-(arylethynyl)adenine and N(6)-methyl or N(6)-(3-substituted-benzyl), were nanomolar full agonists of human (h) A(3)AR and highly selective (K(i) ∼0.6 nM, N(6)-methyl 2-(halophenylethynyl) analo...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Tosh DK,Deflorian F,Phan K,Gao ZG,Wan TC,Gizewski E,Auchampach JA,Jacobson KA

    更新日期:2012-05-24 00:00:00

  • Structure and dynamics of the full-length lipid-modified H-Ras protein in a 1,2-dimyristoylglycero-3-phosphocholine bilayer.

    abstract::Ras proteins regulate signal transduction processes that control cell growth and proliferation. Their disregulation is a common cause of human tumors. Atomic level structural and dynamical information in a membrane environment is crucial for understanding signaling specificity among Ras isoforms and for the design of ...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Gorfe AA,Hanzal-Bayer M,Abankwa D,Hancock JF,McCammon JA

    更新日期:2007-02-22 00:00:00

  • Dual Leucine Zipper Kinase Inhibitors for the Treatment of Neurodegeneration.

    abstract::Dual leucine zipper kinase (DLK, MAP3K12) is an essential driver of the neuronal stress response that regulates neurodegeneration in models of acute neuronal injury and chronic neurodegenerative diseases such as Alzheimer's, Parkinson's, and ALS. In this review, we provide an overview of DLK signaling mechanisms and d...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章,评审


    authors: Siu M,Sengupta Ghosh A,Lewcock JW

    更新日期:2018-09-27 00:00:00

  • Development of Isoselenocyanate Compounds' Syntheses and Biological Applications.

    abstract::As the number of cases and cancer-related deaths are projected to rise in upcoming years, it is urgent to find ways to prevent or treat cancer. As such, food-derived products have gained attention as potential chemopreventive agents due to their availability, safety, and low cost. Isothiocyanates, the breakdown produc...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章,评审


    authors: Frieben EE,Amin S,Sharma AK

    更新日期:2019-06-13 00:00:00

  • Design, synthesis, and binding affinities of potential positron emission tomography (PET) ligands for visualization of brain dopamine D3 receptors.

    abstract::We here report the synthesis of compounds structurally related to the high-affinity dopamine D(3) receptor ligand N-[4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butyl]-7-methoxy-2-benzofurancarboxamide (1). All compounds were specifically designed as potential PET radioligands for brain D(3) receptors visualization, havin...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Leopoldo M,Lacivita E,De Giorgio P,Colabufo NA,Niso M,Berardi F,Perrone R

    更新日期:2006-01-12 00:00:00

  • Design and synthesis of 1-aminocycloalkane-1-carboxylic acid-substituted deltorphin analogues: unique delta and mu opioid activity in modified peptides.

    abstract::Deltorphin analogues were substituted by a series of achiral C alpha,alpha-dialkyl cyclic alpha-amino acids (1-aminocycloalkane-1-carboxylic acids, Ac chi c, where chi = a hexane, pentane, or propane cycloalkane ring) in position 2, 3, 4, or 2 and 3 in deltorphin C, and in position 2 in [Ac6c2,-des-Phe3]deltorphin C h...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Breveglieri A,Guerrini R,Salvadori S,Bianchi C,Bryant SD,Attila M,Lazarus LH

    更新日期:1996-02-02 00:00:00

  • Design, synthesis, and examination of neuron protective properties of alkenylated and amidated dehydro-silybin derivatives.

    abstract::A series of C7-O- and C20-O-amidated 2,3-dehydrosilybin (DHS) derivatives ((+/-)-1a-f and (+/-)-2), as well as a set of alkenylated DHS analogues ((+/-)-4a-f), were designed and de novo synthesized. A diesteric derivative of DHS ((+/-)-3) and two C23 esterified DHS analogues ((+/-)-5a and (+/-)-5b) were also prepared ...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Yang LX,Huang KX,Li HB,Gong JX,Wang F,Feng YB,Tao QF,Wu YH,Li XK,Wu XM,Zeng S,Spencer S,Zhao Y,Qu J

    更新日期:2009-12-10 00:00:00

  • Accurate prediction of the relative potencies of members of a series of kinase inhibitors using molecular docking and MM-GBSA scoring.

    abstract::The ability of molecular docking, using the program Glide and an MM-GBSA postdocking scoring protocol, to correctly rank a number of congeneric kinase inhibitors was assessed. The approach was successful for the cases considered and suggests that this may be useful for the design of inhibitors in the lead optimization...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Lyne PD,Lamb ML,Saeh JC

    更新日期:2006-08-10 00:00:00

  • Abasic site recognition in DNA as a new strategy to potentiate the action of anticancer alkylating drugs?

    abstract::Inhibition of abasic site repair in the cell seems an attractive strategy to potentiate the action of antitumor DNA alkylating drugs. Molecules that bind specifically and strongly to the abasic site are possible candidates to achieve such inhibition. We explored this strategy by preparing molecule 4 that incorporates ...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Belmont P,Jourdan M,Demeunynck M,Constant JF,Garcia J,Lhomme J,Carez D,Croisy A

    更新日期:1999-12-16 00:00:00

  • Pharmacophore based receptor modeling: the case of adenosine A3 receptor antagonists. An approach to the optimization of protein models.

    abstract::To design and synthesize new potent and selective antagonists of the human A(3) adenosine receptor, pharmacophoric hypotheses were generated with the software Catalyst for a comprehensive set of compounds retrieved from previous literature. Three of these pharmacophores were used to drive the optimization of a molecul...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Tafi A,Bernardini C,Botta M,Corelli F,Andreini M,Martinelli A,Ortore G,Baraldi PG,Fruttarolo F,Borea PA,Tuccinardi T

    更新日期:2006-07-13 00:00:00

  • Synthesis of 5'-thymidinyl bis(1-aziridinyl)phosphinates as antineoplastic agents.

    abstract::Reaction of 3'-acetylthymidine with phosphorus oxychloride in trimethyl phosphate yielded the phosphorodichloridate 5, which was subsequently reacted with aziridine, or 2,2-dimethylaziridine to give compounds 6 and 7, respectively. The 2,2-dimethylaziridine derivative 7 was considerably more active than 6 against leuk...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Hsiao LY,Bardos TJ

    更新日期:1981-07-01 00:00:00