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

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 (n(H)) of <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 pL₂ 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.