Binding thermodynamics at the human neuronal nicotine receptor

The thermodynamic parameters Delta G degrees (standard free energy), Delta H degrees (standard enthalpy) and Delta S degrees (standard entropy) of the binding equilibrium of eleven ligands (six agonists and five antagonists) to the neuronal nicotinic receptor were determined by affinity measurements carried out on human thalamus membranes at six different temperatures (0, 10, 20, 25, 30, 35 degrees) and Delta G vs. T plot analysis. Affinity constants were obtained by saturation experiments for [H-3]-cytisine, a ganglionic nicotinic agonist, or its displacement in inhibition assays for the other compounds. The Delta G vs T plots appeared to be reasonably linear in the full temperature range for most of the compounds investigated (equilibrium heat capacity change, Delta C-p degrees approximate to 0), with the exception of the three agonists cytisine, nicotine and methylcarbachol (Delta C-p degrees of the order of -720 divided by -1610 J mol(-1) K-1). Thermodynamic parameters were in the range -53.3 less than or equal to Delta H degrees less than or equal to -28.9 kJ mol(-1) and -41 less than or equal to Delta S degrees less than or equal to 69 J mol(-1) K-1 for agonists, and 8.7 less than or equal to Delta H degrees less than or equal to 68.2 kJ mol(-1) and 99 less than or equal to Delta S degrees 311 J mol(-1) K-1 for antagonists, indicating that agonistic binding was both enthalpy- and entropy-driven, while antagonistic binding was totally entropy-driven. Agonists and antagonists were, therefore, thermodynamically discriminated. Experimental results were discussed with particular regard to the following points: 1) reasons why membrane receptors displayed unusually low values of Delta C-p degrees; 2) possible reasons for the phenomenon of thermodynamic discrimination between agonists and antagonists particularly in connection with ligand gated ion channel receptors; and 3) the origin of the recurrent phenomenon of enthalpy entropy compensation which has been observed for neuronal nicotinic receptor ligands as well as for all membrane receptors studied thus far. (C) 1998 Elsevier Science Inc.