245 words Tables: 6 Figures: 14 Abbreviations: ACh: acetylcholine; AMPA: -Amino-3-hydroxy-5-methyl-4isoxazolepropionic acid; DHPG: 3,4-Dihydroxyphenylglycine; DOPAC: 3,4Dihydroxyphenylacetic acid; GABA: gamma aminobutyric acid; 5-HT: 5-hydroxytryptamine or serotonin; 5-HIAA: 5-hydroxyindolacetic acid; LY341495: (2S)-2-amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl) propanoic acid; mGlu: metabotropic glutamate; LY354740.H2O: (1S,2S,5R,6S) 2Aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid monohydrate; LY379268: (1R,4R,5S,6R)-4-Amino-2-oxabicyclo[3.1.0]hexane-4,6-dicarboxylic acid; LY3020371: (1S,2R,3S,4S,5R,6R)-2-amino-3-[(3,4-difluorophenyl)sulfanylmethyl]-4-hydroxybicyclo[3.1.0]hexane-2,6-dicarboxylic acid; LY3027788: bis(((isopropoxycarbonyl)oxy)methyl) (1S,2R,3S,4S,5R,6R)-2-amino-3-(((3,4-difluorophenyl)thio)methyl)-4-hydroxybicyclo[3.1.0]hexane-2,6-dicarboxylate; MAP2: Microtubule-associated protein; 2NA: noradrenaline or norepinephrine; NPPA: natriuretic peptide A; NBQX: 1,2,3,4tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulfonamide; TMH: tele-methylhistamine or 1-methyl-histamine. This article has not been copyedited and formatted. The final version may differ from this version. JPET Fast Forward. Published on January 30, 2017 as DOI: 10.1124/jpet.116.238121 at A PE T Jornals on A uust 0, 2023 jpet.asjournals.org D ow nladed from

Previous work has suggested that N -methyl- D -aspartate (NMDA) receptor antagonism and 5-hydroxytryptamine (5-HT) 2A receptor blockade may enhance and attenuate, respectively, certain types of impulsivity mediated by corticothalamostriatal circuits. More specifically, past demonstrations of synergistic “antidepressant- like” effects of a 5-HT 2A receptor antagonist and fluoxetine on differential-reinforcement-of-low-rate (DRL) 72-s schedule of op- erant reinforcement may speak to the role of 5-HT 2A receptor blockade with respect to response inhibition as an important prefrontal cortical executive function relating to motor impulsivity. To examine the dynamic range over which 5-HT 2A receptor blockade may exert effects on impulsivity, [ R -( (cid:1) )- (cid:1) -(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl-4-piperidinemethanol](M100907)wasexaminedbothaloneandincombinationwiththepsychotomimeticNMDAreceptorantagonistdizocilpine[e.g.,(

(+)-2-Aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (1), also known as LY354740, is a highly potent and selective agonist for group II metabotropic glutamate receptors (mGlu receptors 2 and 3) tested in clinical trials. It has been shown to block anxiety in the fear-potentiated startle model. Its relatively low bioavailability in different animal species drove the need for an effective prodrug form that would produce a therapeutic response at lower doses for the treatment of anxiety disorders. We have investigated the increase of intestinal absorption of this compound by targeting the human peptide transporter hPepT1 for active transport of di- and tripeptides derived from 1. We have found that oral administration of an N dipeptide derivative of 1 (12a) in rats shows up to an 8-fold increase in drug absorption and a 300-fold increase in potency in the fear-potentiated startle model in rats when compared with the parent drug 1.

ADVERTISEMENT RETURN TO ISSUEPREVLetterNEXTPotent and Selective 1,2,3-Trisubstituted Indole NPY Y-1 AntagonistsPhilip A. Hipskind, Karen L. Lobb, James A. Nixon, Thomas C. Britton, Robert F. Bruns, John Catlow, Donna K. Dieckman-McGinty, Susan L. Gackenheimer, Bruce D. Gitter, Smriti Iyengar, Douglas A. Schober, Rosa M. A. Simmons, Steve Swanson, Hamideh Zarrinmayeh, Dennis M. Zimmerman, and Donald R. GehlertView Author Information Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285Cite this: J. Med. Chem. 1997, 40, 23, 3712–3714Publication Date (Web):November 7, 1997Publication History Received4 August 1997Published online7 November 1997Published inissue 1 November 1997https://pubs.acs.org/doi/10.1021/jm970512xhttps://doi.org/10.1021/jm970512xrapid-communicationACS PublicationsCopyright © 1997 American Chemical SocietyRequest reuse permissionsArticle Views594Altmetric-Citations74LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-AlertscloseSupporting Info (1)»Supporting Information Supporting Information SUBJECTS:Anions,Antagonists,Indoles,Peptides and proteins,Receptors Get e-Alerts

The formation kinetics of 2-hydroxymethyl olanzapine (2-OH olanzapine), 4'-N-oxide olanzapine (N-O olanzapine) and 4'-N-desmethyl olanzapine (NdM olanzapine) were analyzed in vitro. Biphasic kinetics were observed for formation of 2-OH and NdM olanzapine. The high-affinity enzyme responsible for 2-OH olanzapine formation by two human liver samples exhibited an intrinsic clearance (CLint) of 0.2 microliter/min/mg. NdM olanzapine formation by two human liver samples exhibited a CLint of 1.0 microliter/min/mg for the high affinity enzyme. The formation of N-O olanzapine was linear up to 300 microM olanzapine, yielding a CLint of 0.32 to 1.70 microliters/min/mg. The formation of 7-hydroxy olanzapine (7-OH olanzapine) exhibited an apparent Km of 24.2 microM. The rates of 2-OH olanzapine formation correlated with CYP2D6 levels and activity, and it was formed to the greatest extent by cDNA-expressed CYP2D6. N-O olanzapine formation correlated with human liver flavin-containing monooxygenase (FMO3) levels and activity. NdM olanzapine and 7-OH olanzapine formation correlated with CYP1A2 catalytic activities and they were formed to the greatest extent by expressed CYP1A2. These results suggest that CYP1A2 catalyzes NdM olanzapine and 7-OH olanzapine formation, CYP2D6 catalyzes 2-OH olanzapine formation and FMO3 catalyzes N-O olanzapine formation.

LY255582 is a phenylpiperidine opioid antagonist under development as an appetite suppressant and for the treatment of obesity. Female beagles were administered [14C]LY255582 at dosages of 0.72 mg/kg intravenously or 7.2 mg/kg orally. The majority (54-58%) of the radioactivity was eliminated in the urine over 8 days after both oral and intravenous drug administration, primarily as polar metabolites. Peak plasma levels of parent drug in the dog were 11.5 and 311 ng/ml after oral and intravenous administration, respectively, and declined with a half-life of 3.2 hr. Peak plasma levels of LY255582 in the rat were 7.9 and 160 ng/ml after administration of [14C]LY255582 at dosages of 35 mg/kg orally and 1 mg/kg intravenously, respectively. The half-life of parent drug in rats was 1.5 hr; however, the terminal half-lives of radioactivity equivalents were 7.9 and 31.7 hr after intravenous and oral administration, respectively. The bioavailability of parent LY255582 was < 1% in both the rat and the dog, primarily because of extensive first-pass metabolism. Whole-body autoradiographic studies in rats after administration of a single oral 35 mg/kg dose of [14C]LY255582 indicated that radioactivity was rapidly absorbed and distributed throughout the body. Radioactivity concentrated in the liver and was eliminated slowly. Little or no parent drug was eliminated in the urine of either species. As in the urine, the major residues present in the liver and bile of rats orally administered [14C]LY255582 were uncharacterized polar metabolites with little parent drug present.

The disposition of a novel 5HT-1a agonist, LY228729, was studied in rats after oral administration and in monkeys after both iv and oral administration of a radiolabeled drug. Plasma concentrations of LY228729 declined with a half-life of 2.3 and 1.5 hr in monkeys after oral dosing and iv administration, respectively, and 1.9 hr in rats dosed orally. Peak plasma concentrations of the N-despropyl metabolite were greater than the parent drug following oral administration in both rats and monkeys and declined with a half-life of 3.2-3.5 hr. Plasma levels of total radioactivity rapidly exceeded that of the parent drug in both species. Radioactivity was eliminated more slowly, with terminal half-lives of 39.4 hr in the monkey and 48.6 hr in the rat. The parent drug and its despropyl metabolite accounted for only a small percentage of the total radioactivity in the plasma. Following iv and oral administration, radioactivity was eliminated predominantly in the urine of monkeys, but was distributed evenly between the urine and feces of rats. Parent drug and the N-despropyl metabolite were the major products in rat urine. In the monkey, the major metabolite was an uncharacterized polar compound.