ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTN-(1-Oxododecyl)-4.alpha.,10-dimethyl-8-aza-trans-decal-3.beta.-ol: a potent competitive inhibitor of 2,3-oxidosqualene cyclaseM. Woods Wannamaker, Philip P. Waid, William A. Van Sickle, James R. McCarthy, Pamela K. Wilson, Gerald L. Schatzman, and William R. MooreCite this: J. Med. Chem. 1992, 35, 19, 3581–3583Publication Date (Print):September 1, 1992Publication History Published online1 May 2002Published inissue 1 September 1992https://pubs.acs.org/doi/10.1021/jm00097a017https://doi.org/10.1021/jm00097a017research-articleACS PublicationsRequest reuse permissionsArticle Views89Altmetric-Citations21LEARN 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 Get e-Alerts
RMI 11,071 A, one of a series of lactamimides, was found to inhibit the sick-ling rate in an in vitro system. This inhibition was not total or permanent; the sickling rate increased after 30 min at low O2 tension and the number of sickled cells approached that of the controls by 60 min. There was no effect on pH, pCO2, or the oxygen dissociation curve. 45Ca fluxes were affected. Though influx of 45Ca increased on deoxygenation, the compound caused a decrease in 45Ca content on reoxygenation. This decrease was absent in the control group.
A rapid and simple purification of milligram amounts of 2,3-oxidosqualene cyclase, an integral membrane enzyme that catalyzes the cyclization of squalene epoxide to lanosterol, is reported.Several nonionic detergents (Triton X-100, Tween 80, Emulphogene, and lauryl maltoside) were evaluated for solubilization of oxidosqualene cyclase from rat liver microsomes.At a detergent concentration of 5 mg/ml, lauryl maltoside was approximately 10 times more effective than Emulphogene in the solubilization of oxidosqualene cyclase; Triton X-100 and Tween 80 were less effective than Emulphogene as judged by the relative specific activities of the solubilized enzyme.Treatment of microsomes with lauryl maltoside resulted in a selective solubilization of the cyclase with concomitant activation of the enzyme.The solubilized enzyme was purified to homogeneity by fast protein liquid chromatography.The purified enzyme consists of a single subunit that has an apparent molecular weight of 65,000 as determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis.The enzyme obeys saturation kinetics and the apparent K,,, of (2,3)-oxidosqualene is 15 PM; the apparent k J K , is 200 M"*min".An improved assay of the enzyme that utilizes high performance liquid chromatography methods is also described.
(5α,20S)-4-Diazo-2l-hydroxy-20-methylpregnan-3-one, a mechanism-based inhibitor of testosterone 5α-reductase, produced pronounced and long lasting inhibition of the enzyme in the prostate and preputial glands when administered orally to rats. Administration of the inhibitor to castrate rats bearing testosterone implants produced inhibition of growth of the prostate, seminal vesicles, and preputial glands, but had no effect on growth of the levator ani muscle. (5α-20S)-4-Diazo-21-hydroxy-20-methylpregnan-3-one did not antagonize growth of the accessory sex organs induced by 5α-dihydrotestosterone (5α-DHT). The inhibitor thus produced a pure 5α-reductase deficiency in the rat without detectable receptor-level antagonism, and with consequences similar to those occurring at puberty in the 5α-reductase-deficient human male: reduction of 5α-DHT-mediated processes and maintenance of those mediated by testosterone. The results emphasize the importance of the enzymatic profiles of individual organs in determining selective response to testosterone or 5α-DHT. Evidence is presented which indicates that the testes are the source of circulating 5α-DHT in the immature rat. (Endocrinology119: 959–966, 1986)
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTTerminal difluoro olefin analogs of squalene are time-dependent inhibitors of squalene epoxidaseWilliam R. Moore, Gerald L. Schatzman, Esa T. Jarvi, Raymond S. Gross, and James R. McCarthyCite this: J. Am. Chem. Soc. 1992, 114, 1, 360–361Publication Date (Print):January 1, 1992Publication History Published online1 May 2002Published inissue 1 January 1992https://pubs.acs.org/doi/10.1021/ja00027a056https://doi.org/10.1021/ja00027a056research-articleACS PublicationsRequest reuse permissionsArticle Views584Altmetric-Citations116LEARN 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 Get e-Alerts
Since no practical animal model is available for the evaluation of compounds in vivo, we have developed an in vitro model for determining the effect of compounds on the rate of sickling of erythrocytes in whole blood taken from patients with sickle cell anaemia. RMI 6792 (a phenethanol-diamine derivative), procaine, and L-glutamine were tested in this in vitro system. RMI 6792 was tested at various concentrations in whole blood. The data indicate that RMI 6792 decreased the rate of sickling at and above 60 μg/ml. Procaine slightly decreased sickling rate at 100 μg/ml. L-glutamine at 555 μg/ml had no inhibitory effect. RMI 6792 and procaine had no effect on the oxygen dissociation curve. RMI 6792 affected the calcium flux of the erythrocytes and the calcium concentration in the erythrocytes.
