ABSTRACT
A series of hybrid molecules containing the cyclopropylmethylamino side chain found in homotryptamine (1S,2S)-2c and an isosteric heteroaryl or naphthyl core were prepared and their binding affinities for the human serotonin transporter determined. The most potent isosteres were CN-substituted naphthalenes. These results demonstrate that isosteric aromatic cores which lack an H-bond donor site may be substituted for the indole nucleus without substantial loss in hSERT binding.
Subject(s)
Heterocyclic Compounds/chemistry , Heterocyclic Compounds/pharmacology , Selective Serotonin Reuptake Inhibitors/chemistry , Selective Serotonin Reuptake Inhibitors/pharmacology , Tryptamines/chemistry , Dopamine Plasma Membrane Transport Proteins/antagonists & inhibitors , Dopamine Plasma Membrane Transport Proteins/metabolism , Heterocyclic Compounds/chemical synthesis , Humans , Inhibitory Concentration 50 , Molecular Conformation , Norepinephrine Plasma Membrane Transport Proteins/antagonists & inhibitors , Norepinephrine Plasma Membrane Transport Proteins/metabolism , Selective Serotonin Reuptake Inhibitors/chemical synthesis , Structure-Activity RelationshipABSTRACT
To better understand the origin of multivalency effects in ligand binding, the binding of a series of mono-, bi-, tri- and tetravalent carboxylate ligands to Ca(II) was examined by isothermal titration calorimetry (ITC). The data are inconsistent with an entropic origin of enhanced affinity, but rather show that at least in this instance the multivalency effect is enthalpic in origin. Analysis of binding data using the Jencks model shows the addition of incremental carboxylate "ligands" produces an unfavorable interaction entropy that is more than offset by a strongly favorable interaction enthalpy. The most likely source of this interaction enthalpy is the relief of repulsive Coulombic interactions in the unbound state. The conformational entropy penalty arising from the restriction of flexible dihedrals is negligible, within experimental error. On the other hand, an enthalpic contribution from linker restriction contributes strongly to the overall thermodynamics of ligand binding. Together, these data suggest that enthalpic effects dominate ligand binding, and design strategies should seek to optimize these interactions. The incorporation of unfavorable interactions in the unbound ligand that are relieved during binding provides an important mechanism by which to enhance ligand affinities.
