Binding thermodynamics of 5-HT1A receptor ligands

The thermodynamic parameters delta G degree, delta H degree and delta S degree of the binding equilibrium of 15 ligands (eight agonists and seven antagonists) to the 5-HT1A receptor subtype have been determined by affinity measurements carried out on rat cortex membranes (minus striatum) at six different temperatures (0, 10, 20, 25, 30, 35 degrees C), and by van't Hoff plots. Most of the compounds studied are tryptamine, phenylpiperazine and tetralin derivatives. Affinity constants were measured by saturation experiments for the selective 5-HT1A receptor agonist [3H]8-hydroxy-N,N-dipropyl-2-aminotetralin ([3H]8-OH-DPAT) and by inhibition assays of [3H]8-OH-DPAT binding for the other compounds. Scatchard plots were monophasic in the full range of temperatures, indicating a single class of high affinity binding sites. Van't Hoff plots of all ligands were linear in the temperature range investigated (0-30 degrees C or 0-35 degrees C). 5-Hydroxytryptamine (serotonin) and 5-methoxy-tryptamine (mexamine) displayed a positive slope. Experimental data indicate that for 5-HT1A receptor subtype agonists and antagonists are not thermodynamically discriminated. The results are discussed from a quantitative point of view with the aim of obtaining new details on the nature of the forces driving the 5-HT1A binding at a molecular level.