title: Entropy as a factor in the binding of gamma-aminobutyric acid and nipecotic acid to the gamma-aminobutyric acid transport system.
abstract: Nipecotic acid is one of the most potent competitive inhibitors and alternative substrates for the high-affinity gamma-aminobutyric acid transport system in neurons, but the structural basis of this potency is unclear. Because gamma-aminobutyrate is a highly flexible molecule in solution, it would be expected to lose rotational entropy upon binding to the transport system, a change which does not favor binding. Nipecotic acid, in contrast, is a much less flexible molecule, and one would expect the loss of conformational entropy upon binding to be smaller thus favoring the binding of nipecotic acid over gamma-aminobutyric acid. To investigate this possibility, the thermodynamic parameters, delta G degrees, delta H degrees, and delta S degrees, were determined for the binding of gamma-aminobutyrate and nipecotic acid to the high affinity GABA transport system in synaptosomes. In keeping with expectations, the apparent entropy change for nipecotic acid binding (112 +/- 13 J.K-1) was more favorable than the apparent entropy change for gamma-aminobutyric acid binding (61.3 +/- 6.6 J.K-1). The results suggest that restricted conformation per se is an important contributory factor to the affinity of nipecotic acid for the high-affinity transport system for gamma-aminobutyric acid.
authors.affiliation: Upjohn Company, Kalamazoo, MI 49001.
authors.forename: J S
authors.initials: JS
authors.lastname: Althaus
authors.forename: D L
authors.initials: DL
authors.lastname: Martin
mesh_terms: D000818:Animals; D001665:Binding Sites; D001923:Brain Chemistry; D002540:Cerebral Cortex / Q000378:metabolism*; D008297:Male; D008968:Molecular Conformation; D009557:Nipecotic Acids / Q000378:metabolism*; D011392:Proline / Q000031:analogs & derivatives*; D051381:Rats; D011919:Rats, Inbred Strains; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism*; D013574:Synaptosomes; D013696:Temperature; D013816:Thermodynamics; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D009557:Nipecotic Acids; D011963:Receptors, GABA-A; C030278:nipecotic acid; D005680:gamma-Aminobutyric Acid; D011392:Proline; C010983:homoproline