دورية أكاديمية
Receptor reserve masks partial agonist activity of drugs in a cloned rat 5-hydroxytryptamine1B receptor expression system.
| العنوان: | Receptor reserve masks partial agonist activity of drugs in a cloned rat 5-hydroxytryptamine1B receptor expression system. |
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| المؤلفون: | Adham N; Synaptic Pharmaceutical Corporation, Paramus, New Jersey 07652., Ellerbrock B, Hartig P, Weinshank RL, Branchek T |
| المصدر: | Molecular pharmacology [Mol Pharmacol] 1993 Mar; Vol. 43 (3), pp. 427-33. |
| نوع المنشور: | Journal Article; Research Support, U.S. Gov't, P.H.S. |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Society for Pharmacology and Experimental Therapeutics Country of Publication: United States NLM ID: 0035623 Publication Model: Print Cited Medium: Print ISSN: 0026-895X (Print) Linking ISSN: 0026895X NLM ISO Abbreviation: Mol Pharmacol Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Bethesda, MD : American Society for Pharmacology and Experimental Therapeutics |
| مواضيع طبية MeSH: | Adrenergic beta-Antagonists/*pharmacology , Cyclic AMP/*metabolism , Quinolines/*pharmacology , Receptors, Serotonin/*metabolism , Serotonin Receptor Agonists/*pharmacology, Animals ; Binding, Competitive/drug effects ; Cell Line ; Cloning, Molecular ; Colforsin/pharmacology ; Iodocyanopindolol ; Pindolol/analogs & derivatives ; Pindolol/metabolism ; Radioligand Assay ; Rats ; Receptors, Serotonin/genetics ; Serotonin/pharmacology ; Serotonin Receptor Agonists/metabolism ; Transfection ; Virulence Factors, Bordetella/pharmacology |
| مستخلص: | The present study was undertaken to evaluate the behavior of the rat 5-hydroxytryptamine (5-HT)1B receptor stably expressed in a Y-1 cell line, using both radioligand binding ([125I]iodocyanopindolol) and functional assays (inhibition of forskolin-stimulated cAMP release). The measured EC50 values for agonists were lower than expected from the measured Ki values (e.g., 5-HT, EC50 = 0.49 +/- 0.043, nine experiments; Ki = 5.3 +/- 0.82, four experiments). Furthermore, beta-adrenergic antagonists such as propranolol and pindolol, which have been reported to be partial agonists or antagonists at the 5-HT1B receptors in other systems, were found to be full agonists. To investigate the relationship between receptor occupancy and inhibition of cAMP release (and hence the degree of receptor reserve), we used the irreversible receptor antagonist N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ). EEDQ treatment shifted the dose-response curve for 5-HT to the right by 6-7-fold, accompanied by a reduction (30-50%) in maximal response. Analysis of the data by the method of Furchgott revealed a very steep hyperbolic relationship between receptor occupancy and response for 5-HT, with 92 +/- 1.4% (three experiments) receptor reserve at the 50% maximal response level. In contrast to its effect on 5-HT, EEDQ treatment did not significantly shift the dose-response curves for pindolol; rather, only the maximal responses were reduced and a linear relationship was found between receptor occupancy and response for this compound. According to classical receptor theory these data indicate that pindolol is a partial agonist, relative to 5-HT, but because of the high density of 5-HT1B receptors in this system the difference between the intrinsic activities of the two drugs is masked. Therefore, one has to be cautious when interpreting functional data in transfected systems that often display large receptor reserve. |
| معلومات مُعتمدة: | 5 R44 NS277797-03 United States NS NINDS NIH HHS |
| المشرفين على المادة: | 0 (Adrenergic beta-Antagonists) 0 (Quinolines) 0 (Receptors, Serotonin) 0 (Serotonin Receptor Agonists) 0 (Virulence Factors, Bordetella) 1F7A44V6OU (Colforsin) 333DO1RDJY (Serotonin) 60O971AN19 (EEDQ) 83498-72-0 (Iodocyanopindolol) BJ4HF6IU1D (Pindolol) E0399OZS9N (Cyclic AMP) |
| تواريخ الأحداث: | Date Created: 19930301 Date Completed: 19930413 Latest Revision: 20151119 |
| رمز التحديث: | 20240627 |
| PMID: | 8095694 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 0026-895X |
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