Abstract：
: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.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Mosberg HI,Yeomans L,Anand JP,Porter V,Sobczyk-Kojiro K,Traynor JR,Jutkiewicz EMdoi
10.1021/jm5002088subject
Has Abstractpub_date
2014-04-10 00:00:00pages
3148-53issue
7eissn
0022-2623issn
1520-4804journal_volume
57pub_type
杂志文章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
doi：10.1021/jm00219a017
更新日期：1977-09-01 00:00:00
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
doi：10.1021/jm901497b
更新日期：2010-01-28 00:00:00
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
doi：10.1021/jm030926s
更新日期：2003-11-06 00:00:00
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
doi：10.1021/jm00005a012
更新日期：1995-03-03 00:00:00
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
doi：10.1021/jm00173a012
更新日期：1990-11-01 00:00:00
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
doi：10.1021/jm034056q
更新日期：2003-06-19 00:00:00
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
doi：10.1021/jm980388x
更新日期：1999-01-14 00:00:00
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
doi：10.1021/jm00171a042
更新日期：1990-09-01 00:00:00
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
doi：10.1021/jm049508t
更新日期：2005-02-10 00:00:00
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
doi：10.1021/jm00380a001
更新日期：1985-02-01 00:00:00
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
doi：10.1021/jm980299k
更新日期：1998-11-05 00:00:00
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
doi：10.1021/jm00002a009
更新日期：1995-01-20 00:00:00
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
doi：10.1021/jm0009437
更新日期：2000-10-19 00:00:00
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
doi：10.1021/jm00403a024
更新日期：1988-08-01 00:00:00
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
doi：10.1021/jm030951y
更新日期：2004-02-12 00:00:00
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
doi：10.1021/jm0302039
更新日期：2003-12-18 00:00:00
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
doi：10.1021/jm031111m
更新日期：2004-06-03 00:00:00
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
doi：10.1021/jm800149m
更新日期：2008-10-23 00:00:00
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
doi：10.1021/jm400164c
更新日期：2014-03-13 00:00:00
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
doi：10.1021/jm300396n
更新日期：2012-05-24 00:00:00
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
doi：10.1021/jm061053f
更新日期：2007-02-22 00:00:00
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
doi：10.1021/acs.jmedchem.8b00370
更新日期：2018-09-27 00:00:00
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
doi：10.1021/acs.jmedchem.8b01698
更新日期：2019-06-13 00:00:00
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
doi：10.1021/jm050734s
更新日期：2006-01-12 00:00:00
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
doi：10.1021/jm950490j
更新日期：1996-02-02 00:00:00
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
doi：10.1021/jm900735p
更新日期：2009-12-10 00:00:00
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
doi：10.1021/jm060522a
更新日期：2006-08-10 00:00:00
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
doi：10.1021/jm9901428
更新日期：1999-12-16 00:00:00
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
doi：10.1021/jm051112+
更新日期：2006-07-13 00:00:00
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
doi：10.1021/jm00139a024
更新日期：1981-07-01 00:00:00
