title: Dissociable effects of the prodrug phendimetrazine and its metabolite phenmetrazine at dopamine transporters.
abstract: Phendimetrazine (PDM) is a clinically available anorectic and a candidate pharmacotherapy for cocaine addiction. PDM has been hypothesized to function as a prodrug that requires metabolism to the amphetamine-like monoamine transporter substrate phenmetrazine (PM) to produce its pharmacological effects; however, whether PDM functions as an inactive prodrug or has pharmacological activity on its own remains unclear. The study aim was to determine PDM pharmacological mechanisms using electrophysiological, neurochemical, and behavioral procedures. PDM blocked the endogenous basal hDAT (human dopamine transporter) current in voltage-clamped (-60 mV) oocytes consistent with a DAT inhibitor profile, whereas its metabolite PM induced an inward hDAT current consistent with a DAT substrate profile. PDM also attenuated the PM-induced inward current during co-application, providing further evidence that PDM functions as a DAT inhibitor. PDM increased nucleus accumbens dopamine levels and facilitated electrical brain stimulation reinforcement within 10 min in rats, providing in vivo evidence supporting PDM pharmacological activity. These results demonstrate that PDM functions as a DAT inhibitor that may also interact with the pharmacological effects of its metabolite PM. Overall, these results suggest a novel mechanism for PDM therapeutic effects via initial PDM DAT inhibition followed by PM DAT substrate-induced dopamine release.
authors: Department of Physiology and Biophysics, Virginia Commonwealth University, Richmond, VA, 23298 USA.
authors: Ernesto
authors: E
authors: Solis
authors: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, 23298 USA.
authors: Julie A
authors: JA
authors: Suyama
authors: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, 23298 USA.
authors: Matthew F
authors: MF
authors: Lazenka
authors: Department of Physiology and Biophysics, Virginia Commonwealth University, Richmond, VA, 23298 USA.
authors: Louis J
authors: LJ
authors: DeFelice
authors: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, 23298 USA.|Institute for Drug and Alcohol Studies, Virginia Commonwealth University, Richmond, VA, 23298 USA.
authors: S Stevens
authors: SS
authors: Negus
authors: Center for Drug Discovery, Research Triangle Institute, Research Triangle Park, NC, 27709 USA.
authors: Bruce E
authors: BE
authors: Blough
authors: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, 23298 USA.|Institute for Drug and Alcohol Studies, Virginia Commonwealth University, Richmond, VA, 23298 USA.
authors: Matthew L
authors: ML
authors: Banks
mesh_terms: D000818:Animals; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism*; D015536:Down-Regulation; D008297:Male; D015394:Molecular Structure; D009025:Morpholines / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D009714:Nucleus Accumbens / Q000378:metabolism; D009865:Oocytes / Q000187:drug effects* / Q000378:metabolism; D010633:Phenmetrazine / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D014981:Xenopus
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D009025:Morpholines; C100294:phendimetrazine; D004298:Dopamine; D010633:Phenmetrazine