title: Thermodynamics of the binding of BTCP (GK 13) and related derivatives on the dopamine neuronal carrier.
abstract: We have studied the thermodynamic properties of the binding of a coherent series of uptake inhibitors derived from BTCP (GK 13 = N-[1-(2-benzo(b)thiophenyl)cyclohexyl]piperidine) to the dopamine neuronal carrier labelled with [3H]GBR 12783 (1-[2-(diphenylmethoxy)ethyl]4-(3-phenyl-2-propenyl)-piperazine). GK 13 (30 nM) and its 2-naphthyl derivative GK 189 (15 nM) competitively inhibited the specific binding of [3H]GBR 12783 to sites present in rat striatal membranes. Hill numbers calculated for the inhibition of the specific binding of [3H]GBR 12783 by BTCP derivatives were close to 1 (range 0.79-1.18). Increasing the temperature from 0 degrees to 30 degrees C induced a decrease in the affinity of [3H]GBR 12783 and GK derivatives which was generally less pronounced than that obtained when temperature was raised from 30 degrees C to 37 degrees C. Increasing the incubation temperature led to a decrease in both enthalpy (delta H degrees) and entropy (delta S degrees). We observed at 37 degrees C a large negative enthalpy change (range -48, -79 kJ/mol) and a negative, binding unfavorable, change in entropy. This indicates that the GK derivatives binding is enthalpy-driven. Furthermore, data obtained in the present study show that changes in thermodynamic parameters are not a function of the inhibitor's affinity for the dopamine neuronal carrier and this suggests that bonds involved in the inhibitor-carrier interaction are more likely related to the carrier configuration than to the chemical structure of the inhibitor.
authors: EP 076 du C.N.R.S., U.F.R. de Médecine & Pharmacie de Rouen BP 97, Saint Etienne du Rouvray, France.
authors: G
authors: G
authors: Billaud
authors: J F
authors: JF
authors: Menard
authors: N
authors: N
authors: Marcellin
authors: J M
authors: JM
authors: Kamenka
authors: J
authors: J
authors: Costentin
authors: J J
authors: JJ
authors: Bonnet
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D018491:Dopamine Agonists / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins; D066298:In Vitro Techniques; D008297:Male; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D008566:Membranes / Q000378:metabolism; D017072:Neostriatum / Q000378:metabolism; D009419:Nerve Tissue Proteins; D010622:Phencyclidine / Q000031:analogs & derivatives* / Q000378:metabolism; D010879:Piperazines / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D013696:Temperature; D013816:Thermodynamics
chemical_list: D002352:Carrier Proteins; D018491:Dopamine Agonists; D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D010879:Piperazines; C056415:1-(1-(2-benzo(b)thienyl)cyclohexyl)piperidine; C039737:1-(2-(diphenylmethoxy)ethyl)-4-(3-phenyl-2-propenyl)piperazine; D010622:Phencyclidine