DISTINCT THERMODYNAMIC PARAMETERS OF SEROTONIN 5-HT3 AGONISTS AND ANTAGONISTS TO DISPLACE [H-3] GRANISETRON BINDING

Specific binding of [H-3]granisetron was examined to serotonin 5-HT3 r eceptors in synaptosomal membranes of rat cerebral cortex between 1 an d 37 degrees C. Displacing potencies were determined for 5-HT3 antagon ists (granisetron, ondansetron, tropisetron, and d-tubocurarine) and a gonists (5-hydroxytryptamine, 2-methyl-5-hydroxytryptamine, phenylbigu anide, m-chlorophenylbiguanide, and SR 57227A). Displacing potencies o f the agonists decreased with decreasing temperature. In contrast, dis placing potencies of all antagonists increased with decreasing tempera ture, whereas those of tropisetron and d-tubocurarine passed a maximum . Scatchard analysis of [H-3]granisetron binding resulted in K-D value s lower than the IC50 values of granisetron and a decreasing number of binding sites at higher temperatures. It can be reconciled with tempe rature-dependent agonist and antagonist states of 5-HT3 receptors. A s emiquantitative thermodynamic analysis was based on displacing potenci es, The distinct patterns for the signs of entropy, enthalpy, and heat capacity changes on binding can be reconciled with ionic interactions for agonists and hydrophobic interactions for antagonists. The distin ctive differences in these thermodynamic parameters exceed those for G ABA(A) and glycine receptor-ionophore complexes.