Stereoselective Actions of Methylenedioxypyrovalerone (MDPV) To Inhibit Dopamine and Norepinephrine Transporters and Facilitate Intracranial Self-Stimulation in Rats

Abstract

The designer stimulant methylenedioxypyrovalerone (MDPV) is a potent reuptake inhibitor at transporters for dopamine (DAT) and norepinephrine (NET) that produces a constellation of abuse-related behavioral effects. MDPV possesses a chiral center, and the abused formulation of the drug is a racemic mixture, but no data are available on the pharmacology of its isomers. Here, the individual optical isomers of MDPV were prepared and examined with respect to their neurochemical actions on neurotransmitter reuptake and behavioral effects in an assay of intracranial self-stimulation (ICSS) in rats. In assays of DAT uptake inhibition, S(+)MDPV (EC50 = 2.13 nM) was more potent than either (±)MDPV (EC50 = 4.85 nM) or R(-)MDPV (EC50 = 382.80 nM); the three drugs were less potent at NET uptake inhibition, with the same rank order of potency. Neither racemic MDPV nor its optical isomers inhibited the reuptake of serotonin at concentrations up to 10 μM. S(+)MDPV produced an abuse-related and dose-dependent facilitation of ICSS, and the potency of S(+)MDPV (significant facilitation at doses ≥ 0.1 mg/kg) was greater than that of the racemate (significant facilitation at doses ≥ 0.32 mg/kg). R(-)MDPV failed to alter ICSS at doses up to 100 times greater than the lowest effective dose of S(+)MDPV. The results indicate that abuse-related neurochemical and behavioral effects of racemic MDPV reside primarily with its S(+) isomer.

Keywords: DAT; ICSS (intracranial self-stimulation); MDPV; NET; Synthetic cathinones; cocaine; drug abuse; psychomotor stimulants; reuptake inhibition.

Figure 1

Inhibition of [³H]neurotransmitter reuptake at DAT (A) and NET (B) for MDPV (3) and its optical isomers. Data are the mean ± SEM for n = 3 experiments performed in triplicate.

Figure 2

Facilitation of ICSS in rats by S(+)MDPV (0.032–1.0 mg/kg; n = 6) but not by R(−)MDPV (0.32–10 mg/kg; n = 5). (A) The abscissa shows drug dose in mg/kg (log scale; VEH = vehicle), and the ordinate shows rates of ICSS expressed as the percentage of the baseline number of stimulations delivered per component across all brain stimulation frequencies. The asterisk indicates significantly different from VEH, as determined by one-way ANOVA followed by a Dunnett’s posthoc test (p < 0.05). (B, C) The abscissa shows brain stimulation frequency in log Hz, and the ordinate shows rates of ICSS expressed as the percent of the maximum control rate (%MCR), a normalized measure of ICSS reinforcement rate. Filled points indicate significantly different from VEH, as determined by two-way ANOVA followed by the Holm–Sidak posthoc test (p < 0.05).

Scheme 1^a

^a(a) (Boc)₂O, NaHCO₃, dioxane, H₂O, reflux, 24 h; (b) (i) pivaloyl chloride, Et₃N, THF, 0 °C, 1 h, (ii) pyrrolidine, rt, 18 h; (c) 3,4-methylenedioxyphenylmagnesium bromide, THF, rt, 24 h; (d) HCl/dioxane, rt, 20 min; (e) (i) NaBH₄, MeOH, 0 °C, 0.5 h, (ii) HCl/Et₂O; (f) (i) 1,4-dibromobutane, KHCO₃, CH₃CN, reflux, 24 h, (ii) HCl/Et₂O; (g) (i) Jones reagent, 0 °C, 1h, rt, 18 h, (ii) HCl/Et₂O.