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NEUROPHARMACOLOGY

Kinetic and Thermodynamic Assessment of Binding of Serotonin Transporter Inhibitors

Departments of Biochemical Pharmacology (R.S.M., R.A.H., A.S., S.A., B.L., M.E.M.), Pharmaceutics (Z.J.), and Medicinal Chemistry (R.K.K.), Roche Pharmaceuticals, Palo Alto, California

Several serotonin reuptake inhibitors are in clinical use for treatment of depression and anxiety disorders. However, to date, reported pharmacological differentiation of these ligands has focused mainly on their equilibrium binding affinities for the serotonin transporter. This study takes a new look at antidepressant binding modes using radioligand binding assays with [³H]S-citalopram to determine equilibrium and kinetic rate constants across multiple temperatures. The observed dissociation rate constants at 26°C fall into a narrow range for all molecules. Conversely, association rate constants generally decreased with increasing equilibrium binding affinities. Consistent with this, the measured activation energy for S-citalopram association was relatively large (19.5 kcal · mol^-1), suggesting conformational change upon ligand binding. For most of the drugs, including citalopram, the enthalpy (H^O) and entropy (-TS^O) contributions to reaction energetics were determined by van't Hoff analyses to be roughly equivalent (25–75% G^O) and to correlate (positively for enthalpy) with the polar surface area of the drug. However, the binding of the drug fluvoxamine was predominantly entropically driven. When these data are considered in the context of the physicochemical properties of these ligands, two distinct binding modes can be proposed. The citalopram-type binding mode probably uses a polar binding pocket that allows charged or polar interactions between ligand and receptor with comparatively small loss in enthalpy due to dehydration. The fluvoxamine-type binding mode is fueled by energy released upon burying hydrophobic ligand moieties into a binding pocket that is flexible enough to suffer minimal loss in entropy from conformational constraint.

Address correspondence to: Dr. Renee Martin, Roche Pharmaceuticals, 3431 Hillview Ave., Palo Alto CA 94304. E-mail: renee.martin{at}roche.com