The possibility of an allosteric interaction by himbacine, a cardioselective antagonist, with rat cardiac muscarinic receptors was studied. Himbacine allosterically decelerated the dissociation of bound [3H]N-methylscopolamine ([3H]NMS) in a concentration-dependent manner with an IC50 value of 103.7 μM. When compared to the 3C50 values of other cardiovascular antagonists, the rank order of potencies was: methoctramine > gallamine > himbacine > AF-DX 116. In contrast, the potencies of these compounds to displace [3H]NMS binding were: himbacine > methoctramine > AF-DX 116 > gallamine. The allosteric potencies were found not to be correlated with binding potencies (correlation coefficient). = -0.15. A striking common fefeature of the cardioselective anatagonists is their ability to bind to an allosteric site on cardiac muscarinic receptors.
Bibliographical noteFunding Information:
NS-25743 from the National Institutes of Heath and by Contract DAAL03-88-K-0078 from the U.S. Army Research Office. N.H.L. was recipient of an Emerson Fellowship from the University of Maryland during the course of this work. E.E.E.-F. is recipient of a Research Career Development Award from the National Institutes of Health (AG-00344). The authors would like to thank Ms. Donna Bethea for her excellent typing and Mrs. Pat Trener and Mr. Michael Gentry for their assistance.
- Allosteric interaction
- Cardioselective agents
- Muscarinic receptors