Study of auto- and heteroreceptor components of the presynaptic dopamine reuptake modulation in the mechanism of the in vitro action of the novel antiparkinsonian drug hemantane
The effect of Hemantane, a new 2-aminoadamantane derivative (N-adamant-2-ylhexamethylenimine hydrochloride) with antiparkinsonian activity on [3H]-dopamine ([3H]-DA) uptake and binding by D1, D2, and D3 dopamine and NMDA glutamate receptors was studied in comparison with the clinically used drug Amantadine. The method of radioligand binding to rat striatal membrane preparations was used. Both drugs, when used within a concentration range of 10−11 to 10−3 M did not affect the[G-3H]-SCH23390 and [G-3H]-Spiperone binding by D1 and D2 receptors. However, at micromolar concentrations (>10−5 M), Hemantane and Amantadine inhibited the binding of the D3 receptor ligand 7-OH-[G-3H]-DPAT with IC50 values of 39 and 360 μM, respectively; i.e., Hemantane is almost one order of magnitude more efficient. Both preparations exhibited a similar effect on NMDA receptors: the semiinhibition constants IC50 were 5.5 μM for Hemantane and 4 μM for Amantadine. Hemantane and Amantadine were shown to reproducibly inhibit the reuptake of [3H]-dopamine at concentrations of 100–500 μM. The study of inhibition kinetics demonstrated the noncompetitive character of the action: Hemantane decreased the B max value from 9.0 (control) to 5.1 pmol of [3H]-DA per min/mg of protein (p < 0.05), whereas K m value remained constant (0.5 μM), which is characteristic of the noncompetitive type of inhibition. The (±)CPP and MK-801 antagonists of NMDA receptors inhibited the reuptake of [3H]-DA with IC50 of 6 and 38 μM, respectively; NMDA (1, 10, and 100 μM) had no effect; and quisqualate, an agonist of nonNMDA receptors, moderately (−37%, p < 0.05) inhibited dopamine transport at 100 μM. These data seem to indicate that the mechanism of increase of dopaminergic transfer under the action of adamantane derivatives could involve noncompetitive inhibition of dopamine transport.
Key wordsdopamine synaptosomes reuptake NMDA receptors nonNMDA receptors Parkinson’s disease antiparkinsonian drug adamantane derivatives
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