Abstract
Several cholinergic ligands, including a series of methylene-linked bisquaternary ammonium compounds, have been examined for their ability to induce a state transition in the membrane-associated cholinergic receptor where there is a slow increase in affinity for the associating ligand. All of the agonists tested, as well as certain antagonists, notably the metaphiic antagonists, convert the receptor to a higher affinity state. Moreover, the rate of receptor conversion appears to be independent of the ligands’ capacity to activate the receptor. By applying the two-state cyclic scheme used to explain desensitization to these affinity increases, the apparent binding constants of each ligand for the R and R’ receptor states were determined. Full agonists have a 300-fold higher affinity for the R’ state while the classical antagonists (i.e., d-tubocurarine and gallamine) have the same affinity for both receptor states. Apparent negative cooperativity is observed for the antagonists. Partial agonists, which are represented by the methylene-linked bisquaternary series have ratios of affinities for the two states which lie between these extremes. The metaphilic antagonists, which appear to be unique in situ in showing enhanced antagonism for receptors previously conditioned by agonist, will in themselves effect a conversion in receptor state. The structural specificity for the ligands’ capacity to effect a conversion in receptor state lends further support to the contention that the conversion from the low to high affinity state in vitro and receptor desensitization involve the same molecular transition.
ACKNOWLEDGMENTS We thank Drs. R. B. Barlow, H. P. Rang, P. Woodson, C. F. Chignell and R. T. Brittain for their generous donation of compounds essential to this study. The helpful discussions with Mr. S. Sine are gratefully acknowledged. We also thank Mr. Chris Bussineau for synthesis of the bisquaternary methonium compounds.
- Copyright © 1979 by Academic Press, Inc.
MolPharm articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|