Model‐based LFER parameters and QSAR of Ligand β‐Adrenoceptor Interactions II. Estimation and QSAR of Agonistic Potency and Receptor Affinity in a Series of β‐Adrenergic phenethanolamines

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Abstract
Based on an equilibrium model of ligand‐β‐adrenoceptor interactions and β‐adrenergic effectuation presented in a preceding paper, LFER‐related biological parameters to characterize affinity to the receptor and agonistic potency, respectively, are derived for a series of 44 phenethanolamines from measured apparent dissociation constants, KL, and intrinsic activities αACof adenylate cyclase activation. Both parameters result from a decomposition of pKLinto pKL= pKD+ log (1 + K*). Fragment regression analysis of pKLwas used for a preceding separation of the maximal contribution of agonistic interactions to apparent affinity. The log (1 + K*) scale was then estimated as logit transformation of αAC. Hansch analyses of log (1 + K*) and pKDlead to a clear separation of molecular features like substituent positions and interaction types responsible for agonistic potency and affinity, respectively. Thus, both parameters are proved to be of practical value, particularly as the resulting regression coefficients in Hansch equations are directly related to energy contributions of “basic” interaction events.
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