Muscarinic receptors in guinea pig ileum. A study by agonist--3H-labelled antagonist competition.

Abstract

A series of muscarinic agonists (n = 18) derived from dioxolane, furan, piperidine, and thiacyclohexane ring structures which have a degree of conformational restraint have been examined in guinea pig ileal smooth muscle. Binding to muscarinic receptors was determined by competition with 3H-labelled (-)-quinuclidinyl benzilate. Agonist binding was characterized by shallow displacement curves and Hill coefficients (nH) of less than 1. Binding (K1) was resolved into high (K1) and low (K2) affinity components. Correlations between drug-receptor binding and pharmacological activity were examined. A good correlation was found between K1 and K2 (pK1 = 1.33 X pK2 - 0.1), suggesting that the structural requirements for binding at low and high affinity sites are similar. Good correlations also exist between pK1 and pD2 (pK1 = 0.63 X pD2 + 1.27, furans and dioxolanes; pK1 = 0.71 X pD2 + 1.30, piperidines and thiacyclohexanes) confirming that a pharmacologically potent agonist has a high binding affinity. Although K1 represents only an "average" binding affinity its correlation with pD2 is better than those between pK1 or pK2 and pD2. The significance of these several correlations is discussed and some general limitations to the correlation of binding and response data at pharmacological receptors are noted.