دورية أكاديمية
Forskolin carbamates: binding and activation studies with type I adenylyl cyclase.
العنوان: | Forskolin carbamates: binding and activation studies with type I adenylyl cyclase. |
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المؤلفون: | Robbins JD; Center for Biologics Evaluation and Research, Laboratory of Chemical Biology, Food and Drug Administration, Bethesda, Maryland 20892, USA., Boring DL, Tang WJ, Shank R, Seamon KB |
المصدر: | Journal of medicinal chemistry [J Med Chem] 1996 Jul 05; Vol. 39 (14), pp. 2745-52. |
نوع المنشور: | Journal Article |
اللغة: | English |
بيانات الدورية: | Publisher: American Chemical Society Country of Publication: United States NLM ID: 9716531 Publication Model: Print Cited Medium: Print ISSN: 0022-2623 (Print) Linking ISSN: 00222623 NLM ISO Abbreviation: J Med Chem Subsets: MEDLINE |
أسماء مطبوعة: | Publication: Washington Dc : American Chemical Society Original Publication: [Easton, Pa.] : American Chemical Society, [c1963- |
مواضيع طبية MeSH: | Adenylyl Cyclases/*drug effects , Carbamates/*chemical synthesis , Colforsin/*analogs & derivatives, Adenylyl Cyclases/genetics ; Adenylyl Cyclases/metabolism ; Animals ; Carbamates/pharmacology ; Cell Line ; Colforsin/pharmacology ; Enzyme Activation ; Spodoptera |
مستخلص: | Three series of analogs were regioselectively prepared from a protected forskolin precursor to afford 7-carbamoyl-7-desacetylforskolins (series 1), 6-carbamoyl-7-desacetylforskolins (series 2), and 6-carbamoylforskolins (series 3). The analogs were pharmacologically evaluated for binding (IC50) to and activation (EC50) of type I adenylyl cyclase in membranes from stably transfected Sf9 cell lines expressing a single adenylate cyclase subtype. The following ranges were determined for the IC50's and EC50's of each individual series: series 1, IC50 = 43-1600 nM, EC50 = 0.5-9.6 microM; series 2, IC50 = 65-680 nM, EC50 = 0.63-6.5 microM; series 3, IC50 = 21-271 nM, EC50 = 0.5-8.1 microM (forskolin IC50 = 41 nM and EC50 = 0.5 microM). Activation paralleled binding; however, some analogs exhibited poor binding and good activation whereas others demonstrated good binding but poor activation. Steric bulk tended to diminish binding and activation when at the 6- or 7-position, although bulk was accommodated at the 6-position if the 7-site was reacetylated. Acylation of the 7-position by the carbamoyl linker or acetyl was important for obtaining good binding and activation; however, the effect was more pronounced with binding. For both binding and activation, small, linear, lipophilic substituents (propyl, allyl, isopropyl) are well tolerated at the 7-position but less so in the 6-position, even when the 7-site is reacetylated. Planar aromatic moieties (phenyl and 2-pyridinyl) demonstrated moderate to good potency for binding and activation when located at either the 6- or 7-positions. There is an overall trend toward increasing potency for both binding and activation with polar substituents. |
المشرفين على المادة: | 0 (Carbamates) 1F7A44V6OU (Colforsin) EC 4.6.1.1 (Adenylyl Cyclases) |
تواريخ الأحداث: | Date Created: 19960705 Date Completed: 19960910 Latest Revision: 20151119 |
رمز التحديث: | 20231215 |
DOI: | 10.1021/jm960191+ |
PMID: | 8709105 |
قاعدة البيانات: | MEDLINE |
تدمد: | 0022-2623 |
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DOI: | 10.1021/jm960191+ |