High throughput screening of our compound library revealed a series of N-pyridyl-3-benzamides as low micromolar agonists of the human TRPV1 receptor. Synthesis of analogs in this series led to the discovery of a series of N-quinolin-3-yl-benzamides as low nanomolar antagonists of human TRPV1.

A series of structurally simple 7-hydroxynaphthalenyl ureas and amides were discovered to be potent ligands of human vanilloid receptor 1 (VR1). 1-(7-Hydroxynaphthalen-1-yl)-3-(4-trifluoromethylbenzyl)urea 5f exhibited nanomolar binding affinity (Ki=1.0nM) and upon capsaicin challenge, behaved as a potent functional antagonist (IC50=4nM). The synthesis and structure–activity relationships (SARs) for the series are described.

Using a 'directed' iodination procedure, novel iodo-resiniferatoxin congeners were synthesized from 4-acetoxy-3-methoxyphenylacetic acid and resiniferinol- 9,13,14-ortho-phenylacetate (ROPA). The 2-iodo-4-hydroxy-5-methoxyphenylacetic acid ester of resiniferinol 5 displayed high affinity binding (K(i)=0.71 nM) for the human vanilloid VR1 receptor and functioned as a partial agonist.

ADVERTISEMENT RETURN TO ISSUEPREVAddition/CorrectionORIGINAL ARTICLEThis notice is a correctionα2 Adrenoceptor Agonists as Potential Analgesic Agents. 2. Discovery of 4-(4-Imidazo)-1,3-dimethyl-6,7-dihydrothianaphthene as a High-Affinity Ligand for the α2D Adrenergic ReceptorTina M. Ross, Michele C. Jetter, Mark E. McDonnell, Robert E. Boyd, Charlene D. Connelly, Rebecca P. Martinez, Martin A. Lewis, Ellen E. Codd, Robert B. Raffa, and Allen B. ReitzView Author Information Drug Discovery Division, The R. W. Johnson Pharmaceutical Research Institute, Spring House, Pennsylvania 19477 Cite this: J. Med. Chem. 2000, 43, 7, 1423–1426Publication Date (Web):March 24, 2000Publication History Received15 November 1999Published online24 March 2000Published inissue 6 April 2000https://pubs.acs.org/doi/10.1021/jm000128rhttps://doi.org/10.1021/jm000128rcorrectionACS PublicationsCopyright © 2000 American Chemical Society. This publication is available under these Terms of Use. Request reuse permissions This publication is free to access through this site. Learn MoreArticle Views950Altmetric-Citations6LEARN 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 PDF (91 KB) Get e-AlertscloseSupporting Info ()»Supporting Information Supporting Information Get e-Alerts

A novel poly(ethylene terephthalate)–poly(caprolactone) block copolymer (PET–PCL) is synthesized in a reactive twin-screw extrusion process. In the presence of stannous octoate, ring-opening polymerization of ϵ-caprolactone is initiated by the hydroxyl end groups of molten PET to form polycaprolactone blocks. A block copolymer with minimal transesterification is obtained in a twin-screw extruder as a consequence of the fast distributive mixing of ϵ-caprolactone into high melt viscosity PET and the short reaction time. The PET–PCL structure is characterized by IV, GPC, 1H-NMR, and DSC. Fully drawn and partially relaxed fibers spun from PET–PCL are characterized by WAXD and SAXS. A substantial decrease in the oriented amorphous fraction appears to be the major structural change in the relaxed fiber that provides the fiber with the desired stress–strain characteristics. © 1999 John Wiley & Sons, Inc. J Appl Polym Sci 74: 1858–1867, 1999

New antipsychotic drugs are needed because current therapy is ineffective for many schizophrenics and because treatment is often accompanied by extrapyramidal symptoms and dyskinesias. This paper describes the design, synthesis, and evaluation of a series of related (aminomethyl)benzamides in assays predictive of antipsychotic activity in humans. These compounds had notable affinity for dopamine D2, serotonin 5-HT1A, and alpha1-adrenergic receptors. The arylpiperazine 1-[3-[[4-[2-(1-methylethoxy)phenyl]-1-piperazinyl]methyl]benzoyl]p ipe ridine (mazapertine, 6) was chosen because of its overall profile for evaluation in human clinical trials. The corresponding 4-arylpiperidine derivative 67 was also highly active indicating that the aniline nitrogen of 6 is not required for activity. Other particularly active structures include homopiperidine amide 14 and N-methylcyclohexylamide 31.

Several of the key metabolites of mazapertine, a novel antipyschotic agent, were prepared in order to firmly establish their chemical structure and to obtain samples for biological testing. Hydroxymazapertine 3 was synthesized via a multi-step procedure starting from 5-fluoro-2-nitrophenol (8). Alcohol 4 was originally proposed for one of the major metabolites, but the confirmed structure after synthesis was isomer 20.

N1-(2-Alkoxyphenyl)piperazines additionally containing an N4-benzyl group bearing alcohol, amide, imide, or hydantoin functionalities were prepared and evaluated in the conditioned avoidance response (CAR) test predictive of clinical antipsychotic activity and in in vitro receptor-binding assays. Certain of the compounds display high affinity for the D2, 5-HT1A, and alpha 1-adrenergic receptors. Structures bearing acyclic amide, lactam, and imide functionalities display good biological activity, with a preference for the 1,3-disubstituted phenyl ring relative to the 1,4- and 1,2-congeners (7 vs 10 and 12). Every possible position of hydantoin attachment was investigated (e.g., substitution at N1, N3, and C5). The hydantoin involving attachment to N1 (24) was found to have good biological activity, whereas those hydantoins with attachment to N3 or C5 (22, 23, and 25) were inactive. Several of the smaller acetylated derivatives (30 and 33) have fair in vivo activity, which was lost in the case of the larger benzoyl analog 31. Uracil congener 34 had modest affinity for the D2 receptor (65 nM) as well as excellent in vivo activity. Benzylamino compounds display (viz. 27 and 35-38) moderate CAR activity but have surprising receptor affinity, often greater than those of comparable structures bearing a carbonyl (36 vs 7). Benzyl and benzhydryl alcohol compounds 40-48 are more active than amino structures 27 and 35-38 and also exhibit excellent in vivo activity in the CAR test with modest D2 and 5-HT1A receptor binding.

A series of 7,8-disubstituted guanosine derivatives was designed and prepared as potential B-cell-selective activators of the humoral immune response. These compounds were evaluated for their ability to act as B-cell mitogens and to augment the antibody response of B cells to sheep red blood cell (SRBC) challenge (adjuvanticity). In addition, they were tested for their ability to stimulate the natural killer (NK) cell response in murine in vitro cell assays. Certain of the compounds demonstrated in vivo activity when administered either intravenously, subcutaneously, or orally. Analogues with a medium-length alkyl chain (2-4 carbons, 5-7) on the 7-position of 7-alkyl-8-oxoguanosines were found to be particularly potent. Compounds bearing hydroxyalkyl, aminoalkyl, or substituted aminoalkyl substituents on this 7-position were weakly active. However, benzyl groups, including those substituted with heteroatoms (e.g., p-nitrobenzyl, 14), were active. Oxo, thioxo, and seleno groups on C-8 of the guanosine ring all imparted strong activity, whereas other larger substituents did not (e.g., N = CN). Stereochemical inversion of the 2'-hydroxyl on the ribose ring in this series, giving arabinose analogue 70, lessened activity. However, removal of the 2'-hydroxyl, either with (64) or without (73) removal of the 3'-hydroxyl, resulted in excellent activity and improved solubility; 64 also displayed good oral in vivo activity as well. A series of ketals involving the 2',3'-hydroxyls were prepared; certain of the nonpolar ketals (e.g., 48) were remarkably active, pointing to an ancillary hydrophobic binding region that can augment activity. 5'-Phosphate derivative 57 was fairly active, and acyclovir analogue 90 displayed good NK-selective activity: other N-9 sugar mimetics were also active (97-104), although this activity did not carry over into the human B-cell assay. A total of 80 compounds were prepared and evaluated for their immunostimulating activity. Within this group, compounds could be divided into those that were active in all three assays, those that displayed some measure of selectivity for the adjuvanticity assay, and those that preferentially activated NK responses. Because of its overall biological profile and ease of synthesis, 7-allyl-8-oxoguanosine (6; loxoribine, RWJ-21757) was chosen for further development. It is among the most potent compounds evaluated in the three biological assays.

The syntheses of new ferrocene substituted pyrroles has been carried out by the reaction of TosMIC with an alpha, beta-unsaturated ferrocene derivative.

The aim of the present work is to investigate the conformational change of conjugated chains upon doping by small angle neutron scattering. Polymer solutions such as n-butylthiophene (C 4 HS(CH 2 ) 3 CH 3 ) n doped with NOSbF 6 can provide such a goal. For the neutral chains, results show that, at room temperature, even for the lowest polymer concentration studied (c p = 0.1 mg/cc), a positive interchain interaction occurs. At higher temperature (T = 65°C), an isolated chain behavior can be measured allowing to measure the statistical length b = 55 A ̊ and the extension of the lateral groups L t = 12 A ̊ . With a polymer concentrationsas low as c p = 0.5 mg/cc and a dopant concentration equivalent to one dopant molecule per monomer unit, the chain conformation is modeled by a rod structure, b > 850 A ̊ . At the same dopant concentration, but with c p = 2.4 mg/cc, the scattering function show a q −2 behavior. In any case, no correlation hole is observed, which differs markedly from the usual behavior observed in polyelectrolyte solutions.

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTScaling analysis of static properties for semidilute solutionsJafar Amirzadeh and Milton E. McDonnellCite this: Macromolecules 1982, 15, 3, 927–933Publication Date (Print):May 1, 1982Publication History Published online1 May 2002Published inissue 1 May 1982https://pubs.acs.org/doi/10.1021/ma00231a045https://doi.org/10.1021/ma00231a045research-articleACS PublicationsRequest reuse permissionsArticle Views41Altmetric-Citations12LEARN 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-Alertsclose Get e-Alerts