Method for Comparing Selectivities of Unlabeled Subpopulation-Selective Ligands: Application to Muscarinic Receptors

Abstract

A method for comparing the selectivities of two unlabeled ligands by simultaneous competition for the binding of a nonselective labeled ligand has been illustrated by computer simulations. Experimental application of this approach indicated that the subpopulations of muscarinic receptors that are distinguished by the use of quaternary antagonists are not related to the M₁ and M₂ subtypes (based on pirenzepine). However, the quaternary agonist carbachol was found to express both modes of selectivity.

The method should be particularly useful in the evaluation of new ligands when labeled selective ligands are unavailable. Further, this method complements experiments that can be carried out with a labeled selective ligand, since it emphasizes the contribution of the sites for which the selective ligand has low affinity.