Abstract:
:The binding kinetics of [3H]Ro 15-1788, a selective benzodiazepine receptor antagonist, to synaptosomal membranes of rat cerebral cortices was studied. [3H]Ro 15-1788 binds with high affinity (dissociation constant, 0.53 nM) to a single class of binding sites (maximal binding capacity, 1.97 pmoles/mg of protein). Equilibrium binding was not affected by gamma-aminobutyric acid (GABA), NaCl, pentobarbital, or pretreatment of the membranes at 37 degrees. Association at 0 degrees was identical whether measured in the absence or presence of GABA or bicuculline methiodide or after preincubation of the membranes at 37 degrees. The association rate under pseudo-first order conditions was curvilinear and consisted of a fast component and a slow component. Dissociation at 0 degrees with 1 X 10(-5)M clonazepam was also curvilinear and could best be fitted by two linear exponential components. The dissociation rate was not altered by GABA, NaCl, pentobarbital, or pretreatment of membranes at 37 degrees. The dissociation rate was similar for 0.1, 1, and 10 nM [3H]Ro 15-1788. The ratio of slow to fast dissociation component for 10 nM [3H]Ro 15-1788 was larger than that for 0.1 and 1 nM [3H]Ro 15-1788. In contrast, the dissociation rate for 20 nM [3H]flunitrazepam ( [3H]FNP) was much greater than that for 2 nM [3H]FNP. Using ligand concentrations occupying the same fraction of receptors, the ratio of slow to fast dissociation components was invariably greater for [3H]Ro 15-1788 than that for [3H]FNP. The rate of dissociation for [3H]Ro 15-1788 was faster under pre-equilibrium conditions than under equilibrium conditions. These results, discussed in terms of the cyclic model of interaction between receptors and benzodiazepines, suggest that [3H]Ro 15-1788 is a powerful ligand in inducing conformational changes in the initial, more labile, binary complex. They also suggest that different conformational states deduced from studies of in vitro binding kinetics may not correspond to the distinct pharmacological actions of benzodiazepines. It is speculated that intrinsic activities of benzodiazepines probably are determined by the step beyond the complex formation and conformational changes suggested to occur by these studies of binding kinetics.
journal_name
Mol Pharmacoljournal_title
Molecular pharmacologyauthors
Chiu TH,Rosenberg HCsubject
Has Abstractpub_date
1983-03-01 00:00:00pages
289-94issue
2eissn
0026-895Xissn
1521-0111journal_volume
23pub_type
杂志文章abstract::The interaction of [3H]acetylcholine ([3H]AcCh) with the muscarinic receptor was studied in seven distinct rat brain regions and in heart atrium by employing 10 microM atropine to define specific binding. The specific binding exhibited by the labeled neurotransmitter was found to be sensitive to muscarinic but not to ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
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journal_title:Molecular pharmacology
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journal_title:Molecular pharmacology
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更新日期:1993-04-01 00:00:00
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更新日期:1999-03-01 00:00:00
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journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1982-03-01 00:00:00
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pub_type: 评论,杂志文章
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journal_title:Molecular pharmacology
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更新日期:1991-09-01 00:00:00
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journal_title:Molecular pharmacology
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更新日期:1996-06-01 00:00:00
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journal_title:Molecular pharmacology
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更新日期:1986-01-01 00:00:00
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journal_title:Molecular pharmacology
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更新日期:1989-04-01 00:00:00
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更新日期:1991-10-01 00:00:00
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更新日期:1999-10-01 00:00:00
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