Abstract
A sep. consideration of ligand-b-adrenoceptor interactions responsible for affinity (recognition, binding) and agonistic activity, resp., is very important for the explanation of mol. events eliciting the activating conformational change of the receptor. Equil. models of b-adrenergic effectuation including receptor activation by agonists and partial agonists, receptor-effector (G-protein) ...
Abstract
A sep. consideration of ligand-b-adrenoceptor interactions responsible for affinity (recognition, binding) and agonistic activity, resp., is very important for the explanation of mol. events eliciting the activating conformational change of the receptor. Equil. models of b-adrenergic effectuation including receptor activation by agonists and partial agonists, receptor-effector (G-protein) coupling, and adenylate cyclase stimulation yield LFER-related parameters of both interaction components from apparent dissocn. consts. and intrinsic activities. Two models, both contg. precoupling of non-activated receptor and effector mols., are derived, i.e. a ternary complex model for the interactions of ligands, receptor, and effector in the absence, and an adenylate cyclase activation model for enzyme activation in the presence of GTP. Agonistic activity is represented by the equil. const. K* reflecting the concn. ratio of activated and non-activated agonist-receptor complexes. KD, The dissocn. const. of non-activated complexes, represents ligand-receptor recognition and binding. K* can be estd. either from using ratios KL/KH of apparent low- and high affinity dissocn. consts. in GTP absence, or from using intrinsic activities of adenylate cyclase activation. According to those models, KL, which also describes apparent dissocn. in binding assays with GTP, is related to KD and K* by KL = KD/(1 + K*). In terms of the free energy ligand binding and receptor activation, DGo = RT ln KL, this corresponds to a decompn. of pKL into pKL = pKD + log (1 + K*). In QSAR, thus, log (1 + K*) is the parameter of choice for LFER-related description of ligand-receptor interactions eliciting agonistic activity.
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