Regional differences in receptor reserve for analogs of oxotremorine in vivo: implications for development of selective muscarinic agonists
The muscarinic actions of several analogs of oxotremorine were compared in the mouse. Compounds such as AKS 19 and BM 5 having low intrinsic efficacy (partial agonists) differentiated between centrally mediated muscarinic effects as they, like oxotremorine, were potent in producing analgesia and hyp...
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Published in | The Journal of pharmacology and experimental therapeutics Vol. 242; no. 2; pp. 464 - 471 |
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Main Authors | , , |
Format | Journal Article |
Language | English |
Published |
Bethesda, MD
American Society for Pharmacology and Experimental Therapeutics
01.08.1987
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Subjects | |
Online Access | Get full text |
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Summary: | The muscarinic actions of several analogs of oxotremorine were compared in the mouse. Compounds such as AKS 19 and BM 5 having
low intrinsic efficacy (partial agonists) differentiated between centrally mediated muscarinic effects as they, like oxotremorine,
were potent in producing analgesia and hypothermia but did not produce tremor. Instead they antagonized oxotremorine-induced
tremor. They resembled oxotremorine in their ability to stimulate salivary secretion. Excellent correlations were found between
the various muscarinic effects measured in vivo and spasmogenic activity on the guinea pig ileum and between tremorolytic
potency and affinity for ileal muscarinic receptors. The results suggest that there are regional differences in the receptor
reserve for muscarinic agonists that may affect in vivo responses to partial agonists in a qualitative manner. Responses to
more efficacious agonists such as oxotremorine are affected only quantitatively by such differences. Efficacious agonists
appeared to have a large receptor reserve with respect to salivation, analgesia and hypothermia, whereas their receptor reserve
for the tremor response was lower. The possibility is raised of achieving selective muscarinic actions, even in the absence
of distinct subtypes of muscarinic receptors, by exploiting regional differences in receptor density, in the efficiency of
receptor-effector coupling and in endogenous levels of acetylcholine. |
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ISSN: | 0022-3565 1521-0103 |