Structural requirements for muscarinic receptor occupation and receptor activation by oxotremorine analogs in the guinea-pig ileum
The muscarinic activities in the isolated guinea-pig ileum of nine analogs of oxotremorine, modified only in the amino group, were resolved into affinity and efficacy components. The method used involved analysis of dose-response data before and after fractional inactivation of receptors with propyl...
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Published in | The Journal of pharmacology and experimental therapeutics Vol. 232; no. 1; pp. 67 - 73 |
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Main Author | |
Format | Journal Article |
Language | English |
Published |
Bethesda, MD
American Society for Pharmacology and Experimental Therapeutics
01.01.1985
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Subjects | |
Online Access | Get full text |
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Summary: | The muscarinic activities in the isolated guinea-pig ileum of nine analogs of oxotremorine, modified only in the amino group,
were resolved into affinity and efficacy components. The method used involved analysis of dose-response data before and after
fractional inactivation of receptors with propylbenzilylcholine mustard. The dissociation constants (KA) thus obtained for
oxotremorine (6.79 X 10(-7) M), oxotremorine methiodide (6.74 X 10(-6) M) and oxotremorine-M (2.92 X 10(-6) M) agreed well
with their reported low-affinity dissociation constants (KL) determined in receptor binding studies. There was no correlation
between relative affinities and efficacies of the nine agonists studied, suggesting different structural requirements for
occupation and activation of muscarinic receptors in the guinea-pig ileum. Although oxotremorine had higher affinity than
its analogs, some of the latter had substantially greater efficacy than oxotremorine. Thus, replacement of the pyrrolidine
ring of oxotremorine by azetidino, dimethylamino or trimethylammonium groups was accompanied by a 4- to 7-fold increase in
efficacy. A diethylamino group in place of pyrrolidine gave an 18-fold decrease in efficacy and a triethylammonium group abolished
efficacy. The relative efficacies of the nine agonists were inversely correlated with the size of the amino or ammonium group.
No significant correlation was observed between relative affinities for the receptor and size of the cationic head. |
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Bibliography: | ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2 |
ISSN: | 0022-3565 1521-0103 |