European journal of pharmacology

Thermodynamics of the binding of BTCP (GK 13) and related derivatives on the dopamine neuronal carrier.

PMID 7805759


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.

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BTCP hydrochloride
C19H25NS · HCl