The Alkylamine Stimulant 1,3-Dimethylamylamine Exhibits Substrate-Like Regulation of Dopamine Transporter Function and Localization.

Humans Dopamine Plasma Membrane Transport Proteins / metabolism Appetite Depressants Dopamine / metabolism Cocaine / pharmacology Amphetamine / pharmacology Central Nervous System Agents

Journal

The Journal of pharmacology and experimental therapeutics
ISSN: 1521-0103
Titre abrégé: J Pharmacol Exp Ther
Pays: United States
ID NLM: 0376362

Informations de publication

Date de publication:
08 2023
Historique:
received: 30 12 2022
accepted: 04 05 2023
pmc-release: 01 08 2024
medline: 19 7 2023
pubmed: 23 6 2023
entrez: 22 6 2023
Statut: ppublish

Résumé

The alkylamine stimulant 1,3-dimethylamylamine (DMAA) is used nonmedically as an appetite suppressant and exercise performance enhancer despite adverse cardiovascular effects that have limited its legal status. There is scant research describing the mechanism of action of DMAA, making it difficult to gauge risks or therapeutic potential. An important molecular target of structurally related phenethylamines, such as amphetamine, for regulating mood, cognition, movement, and the development of substance use disorder is the dopamine transporter, which limits the range and magnitude of dopamine signaling via reuptake from the extracellular space. The present studies were therefore initiated to characterize the effects of DMAA on dopamine transporter function. Specifically, we tested the hypothesis that DMAA exhibits substrate-like effects on dopamine transporter function and trafficking. In transport assays in human embryonic kidney cells, DMAA inhibited dopamine uptake by the human dopamine transporter in a competitive manner. Docking analysis and molecular dynamics simulations supported these findings, revealing that DMAA binds to the S1 substrate binding site and induces a conformational change from outward-facing open to outward-facing closed states, similar to the known substrates. Further supporting substrate-like effects of DMAA, the drug stimulated dopamine transporter endocytosis in a heterologous expression system via cocaine- and protein kinase A-sensitive mechanisms, mirroring findings with amphetamine. Together, these data indicate that DMAA elicits neurologic effects by binding to and regulating function of the dopamine transporter. Furthermore, pharmacologic distinctions from amphetamine reveal structural determinants for regulating transporter conformation and add mechanistic insight for the regulation of dopamine transporter endocytosis. SIGNIFICANCE STATEMENT: The alkylamine stimulant 1,3-dimethylamylamine (DMAA) is used as an appetite suppressant and athletic performance enhancer and is structurally similar to amphetamine, but there is scant research describing its mechanism of action. Characterizing the effects of DMAA on dopamine transporter function supports evaluation of potential risks and therapeutic potential while also revealing mechanistic details of dynamic transporter-substrate interactions.

Identifiants

DOI: 10.1124/jpet.122.001573 PMID: 37348963 PMC: PMC10353075
pubmed: 37348963
pii: jpet.122.001573
doi: 10.1124/jpet.122.001573
pmc: PMC10353075
doi:

Substances chimiques

1,3-dimethylamylamine 0
Dopamine Plasma Membrane Transport Proteins 0
Appetite Depressants 0
Dopamine VTD58H1Z2X
Cocaine I5Y540LHVR
Amphetamine CK833KGX7E
Central Nervous System Agents 0

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

266-273

Subventions

Organisme : NIDA NIH HHS
ID : R01 DA014204
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM139297
Pays : United States

Informations de copyright

Copyright © 2023 by The American Society for Pharmacology and Experimental Therapeutics.

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Auteurs

Cassandra Small (C)

Science Department, Chatham University, Pittsburgh, Pennsylvania (C.S., S.S.B., S.L.B., B.Z., E.R.B.) and Departments of Computational and Systems Biology (M.H.C.) and Cell Biology (A.S.), School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.

Mary Hongying Cheng (MH)

Science Department, Chatham University, Pittsburgh, Pennsylvania (C.S., S.S.B., S.L.B., B.Z., E.R.B.) and Departments of Computational and Systems Biology (M.H.C.) and Cell Biology (A.S.), School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.

Saron S Belay (SS)

Science Department, Chatham University, Pittsburgh, Pennsylvania (C.S., S.S.B., S.L.B., B.Z., E.R.B.) and Departments of Computational and Systems Biology (M.H.C.) and Cell Biology (A.S.), School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.

Sarah L Bulloch (SL)

Science Department, Chatham University, Pittsburgh, Pennsylvania (C.S., S.S.B., S.L.B., B.Z., E.R.B.) and Departments of Computational and Systems Biology (M.H.C.) and Cell Biology (A.S.), School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.

Brooke Zimmerman (B)

Science Department, Chatham University, Pittsburgh, Pennsylvania (C.S., S.S.B., S.L.B., B.Z., E.R.B.) and Departments of Computational and Systems Biology (M.H.C.) and Cell Biology (A.S.), School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.

Alexander Sorkin (A)

Science Department, Chatham University, Pittsburgh, Pennsylvania (C.S., S.S.B., S.L.B., B.Z., E.R.B.) and Departments of Computational and Systems Biology (M.H.C.) and Cell Biology (A.S.), School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.

Ethan R Block (ER)

Science Department, Chatham University, Pittsburgh, Pennsylvania (C.S., S.S.B., S.L.B., B.Z., E.R.B.) and Departments of Computational and Systems Biology (M.H.C.) and Cell Biology (A.S.), School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania eblock@chatham.edu.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › The Alkylamine Stimulant 1,3-Dimethylamylamine...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Protéines de transport membranaire › Protéines transporteurs de solutés › Transporteurs de la dopamine › The Alkylamine Stimulant 1,3-Dimethylamylamine...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Utilisations thérapeutiques › Agents antiobésité › Anorexigènes › The Alkylamine Stimulant 1,3-Dimethylamylamine...
questionsmedicales.fr › Composés chimiques organiques › Hydrocarbures › Hydrocarbures cycliques › Hydrocarbures aromatiques › Dérivés du benzène › Phénols › Catéchols › Catécholamines › Dopamine › The Alkylamine Stimulant 1,3-Dimethylamylamine...
questionsmedicales.fr › Composés hétérocycliques › Composés hétérocycliques, cycle ponté › Tropanes › Cocaïne › The Alkylamine Stimulant 1,3-Dimethylamylamine...
questionsmedicales.fr › Composés chimiques organiques › Amines › Éthylamines › Phénéthylamines › Amphétamines › Amfétamine › The Alkylamine Stimulant 1,3-Dimethylamylamine...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Utilisations thérapeutiques › Agents du système nerveux central › The Alkylamine Stimulant 1,3-Dimethylamylamine...