title: 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.
authors: †Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, 800 East Leigh Street, PO Box 980540, Richmond, Virginia 23298, United States.
authors: R
authors: R
authors: Kolanos
authors: ‡Designer Drug Research Unit, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland 21224, United States.
authors: J S
authors: JS
authors: Partilla
authors: ‡Designer Drug Research Unit, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland 21224, United States.
authors: M H
authors: MH
authors: Baumann
authors: §Department of Pharmacology and Toxicology, Virginia Commonwealth University, 410 North 12th Street, PO Box 980613, Richmond, Virginia 23298, United States.
authors: B A
authors: BA
authors: Hutsell
authors: §Department of Pharmacology and Toxicology, Virginia Commonwealth University, 410 North 12th Street, PO Box 980613, Richmond, Virginia 23298, United States.
authors: M L
authors: ML
authors: Banks
authors: §Department of Pharmacology and Toxicology, Virginia Commonwealth University, 410 North 12th Street, PO Box 980613, Richmond, Virginia 23298, United States.
authors: S S
authors: SS
authors: Negus
authors: †Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, 800 East Leigh Street, PO Box 980540, Richmond, Virginia 23298, United States.
authors: R A
authors: RA
authors: Glennon
mesh_terms: D000818:Animals; D052117:Benzodioxoles / Q000737:chemistry* / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects*; D015198:Designer Drugs / Q000737:chemistry / Q000494:pharmacology; D050483:Dopamine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors*; D008297:Male; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors*; D011759:Pyrrolidines / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012653:Self Stimulation / Q000187:drug effects; D013237:Stereoisomerism; D000094982:Synthetic Cathinone
chemical_list: D052117:Benzodioxoles; D015198:Designer Drugs; D050483:Dopamine Plasma Membrane Transport Proteins; D050484:Norepinephrine Plasma Membrane Transport Proteins; D011759:Pyrrolidines; D000094982:Synthetic Cathinone
keywords: DAT; ICSS (intracranial self-stimulation); MDPV; NET; Synthetic cathinones; cocaine; drug abuse; psychomotor stimulants; reuptake inhibition