Structural and stereochemical requirements for muscarinic receptor binding

The ability of stereoisomers of muscarinic agonists and antagonists to inhibit specific [³H](DL)3-quinuclidinyl benzilate binding to receptors in rat brain and guinea pig ileum longitudinal muscle is compared to their ability to stimulate or inhibit contraction of the ileum longitudinal muscle. The close correlations observed with receptor antagonists and weak agonists emphasize the equivalence of muscarinic receptors identified by biochemical and physiological techniques. The correlations with the most biologically potent agonists were poor, suggesting high intrinsic activity and large spare receptor populations for these compounds. Muscarinic receptors display stereoselectivity with the enantiomers of certain strong agonists in their production of ileum muscle contractions but not in their ability to inhibit [³H](DL)3-quinuclidinyl benzilate binding. Although minor differences are observed between binding stereoselectivity in the muscle and brain tissues, the results suggest a similar structural geometry in the two receptors.