Structure-activity relationships of bath salt components: substituted cathinones and benzofurans at biogenic amine transporters

Amy J. Eshleman, Shanthi Nagarajan, Katherine M. Wolfrum, John F. Reed, Tracy L. Swanson, Aaron Nilsen, Aaron Janowsky

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Rationale: New psychoactive substances (NPSs), including substituted cathinones and other stimulants, are synthesized, sold on the Internet, and ingested without knowledge of their pharmacological activity and/or toxicity. In vitro pharmacology plays a role in therapeutic drug development, drug-protein in silico interaction modeling, and drug scheduling. Objectives: The goal of this research was to determine mechanisms of action that may indicate NPS abuse liability. Methods: Affinities to displace the radioligand [125I]RTI-55 and potencies to inhibit [3H]neurotransmitter uptake for 22 cathinones, 6 benzofurans and another stimulant were characterized using human embryonic kidney cells stably expressing recombinant human transporters for dopamine, norepinephrine, or serotonin (hDAT, hNET, or hSERT, respectively). Selected compounds were tested for potencies and efficacies at inducing [3H]neurotransmitter release via the transporters. Computational modeling was conducted to explain plausible molecular interactions established by NPS and transporters. Results: Most α-pyrrolidinophenones had high hDAT potencies and selectivities in uptake assays, with hDAT/hSERT uptake selectivity ratios of 83–360. Other substituted cathinones varied in their potencies and selectivities, with N-ethyl-hexedrone and N-ethyl-pentylone having highest hDAT potencies and N-propyl-pentedrone having highest hDAT selectivity. 4-Cl-ethcathinone and 3,4-methylenedioxy-N-propylcathinone had higher hSERT selectivity. Benzofurans generally had low hDAT selectivity, especially 1-(2,3-dihydrobenzofuran-5-yl)-N-methylpropan-2-amine, with 25-fold higher hSERT potency. Consistent with this selectivity, the benzofurans were releasers at hSERT. Modeling indicated key amino acids in the transporters’ binding pockets that influence drug affinities. Conclusions: The α-pyrrolidinophenones, with high hDAT selectivity, have high abuse potential. Lower hDAT selectivity among benzofurans suggests similarity to methylenedioxymethamphetamine, entactogens with lower stimulant activity.

Original languageEnglish (US)
JournalPsychopharmacology
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

Benzofurans
Biogenic Amines
Structure-Activity Relationship
Baths
Salts
Neurotransmitter Agents
Pharmaceutical Preparations
Pharmacology
Norepinephrine Plasma Membrane Transport Proteins
Amino Acid Transport Systems
N-Methyl-3,4-methylenedioxyamphetamine
Serotonin Plasma Membrane Transport Proteins
Dopamine Plasma Membrane Transport Proteins
Drug Design
Drug Interactions
Internet
Computer Simulation
Substance-Related Disorders
Amines
Kidney

Keywords

  • Benzofurans
  • Cathinones
  • New psychoactive substances
  • Pharmacology
  • Psychostimulant
  • Transporter

ASJC Scopus subject areas

  • Pharmacology

Cite this

Structure-activity relationships of bath salt components : substituted cathinones and benzofurans at biogenic amine transporters. / Eshleman, Amy J.; Nagarajan, Shanthi; Wolfrum, Katherine M.; Reed, John F.; Swanson, Tracy L.; Nilsen, Aaron; Janowsky, Aaron.

In: Psychopharmacology, 01.01.2018.

Research output: Contribution to journalArticle

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abstract = "Rationale: New psychoactive substances (NPSs), including substituted cathinones and other stimulants, are synthesized, sold on the Internet, and ingested without knowledge of their pharmacological activity and/or toxicity. In vitro pharmacology plays a role in therapeutic drug development, drug-protein in silico interaction modeling, and drug scheduling. Objectives: The goal of this research was to determine mechanisms of action that may indicate NPS abuse liability. Methods: Affinities to displace the radioligand [125I]RTI-55 and potencies to inhibit [3H]neurotransmitter uptake for 22 cathinones, 6 benzofurans and another stimulant were characterized using human embryonic kidney cells stably expressing recombinant human transporters for dopamine, norepinephrine, or serotonin (hDAT, hNET, or hSERT, respectively). Selected compounds were tested for potencies and efficacies at inducing [3H]neurotransmitter release via the transporters. Computational modeling was conducted to explain plausible molecular interactions established by NPS and transporters. Results: Most α-pyrrolidinophenones had high hDAT potencies and selectivities in uptake assays, with hDAT/hSERT uptake selectivity ratios of 83–360. Other substituted cathinones varied in their potencies and selectivities, with N-ethyl-hexedrone and N-ethyl-pentylone having highest hDAT potencies and N-propyl-pentedrone having highest hDAT selectivity. 4-Cl-ethcathinone and 3,4-methylenedioxy-N-propylcathinone had higher hSERT selectivity. Benzofurans generally had low hDAT selectivity, especially 1-(2,3-dihydrobenzofuran-5-yl)-N-methylpropan-2-amine, with 25-fold higher hSERT potency. Consistent with this selectivity, the benzofurans were releasers at hSERT. Modeling indicated key amino acids in the transporters’ binding pockets that influence drug affinities. Conclusions: The α-pyrrolidinophenones, with high hDAT selectivity, have high abuse potential. Lower hDAT selectivity among benzofurans suggests similarity to methylenedioxymethamphetamine, entactogens with lower stimulant activity.",
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author = "Eshleman, {Amy J.} and Shanthi Nagarajan and Wolfrum, {Katherine M.} and Reed, {John F.} and Swanson, {Tracy L.} and Aaron Nilsen and Aaron Janowsky",
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T2 - substituted cathinones and benzofurans at biogenic amine transporters

AU - Eshleman, Amy J.

AU - Nagarajan, Shanthi

AU - Wolfrum, Katherine M.

AU - Reed, John F.

AU - Swanson, Tracy L.

AU - Nilsen, Aaron

AU - Janowsky, Aaron

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Rationale: New psychoactive substances (NPSs), including substituted cathinones and other stimulants, are synthesized, sold on the Internet, and ingested without knowledge of their pharmacological activity and/or toxicity. In vitro pharmacology plays a role in therapeutic drug development, drug-protein in silico interaction modeling, and drug scheduling. Objectives: The goal of this research was to determine mechanisms of action that may indicate NPS abuse liability. Methods: Affinities to displace the radioligand [125I]RTI-55 and potencies to inhibit [3H]neurotransmitter uptake for 22 cathinones, 6 benzofurans and another stimulant were characterized using human embryonic kidney cells stably expressing recombinant human transporters for dopamine, norepinephrine, or serotonin (hDAT, hNET, or hSERT, respectively). Selected compounds were tested for potencies and efficacies at inducing [3H]neurotransmitter release via the transporters. Computational modeling was conducted to explain plausible molecular interactions established by NPS and transporters. Results: Most α-pyrrolidinophenones had high hDAT potencies and selectivities in uptake assays, with hDAT/hSERT uptake selectivity ratios of 83–360. Other substituted cathinones varied in their potencies and selectivities, with N-ethyl-hexedrone and N-ethyl-pentylone having highest hDAT potencies and N-propyl-pentedrone having highest hDAT selectivity. 4-Cl-ethcathinone and 3,4-methylenedioxy-N-propylcathinone had higher hSERT selectivity. Benzofurans generally had low hDAT selectivity, especially 1-(2,3-dihydrobenzofuran-5-yl)-N-methylpropan-2-amine, with 25-fold higher hSERT potency. Consistent with this selectivity, the benzofurans were releasers at hSERT. Modeling indicated key amino acids in the transporters’ binding pockets that influence drug affinities. Conclusions: The α-pyrrolidinophenones, with high hDAT selectivity, have high abuse potential. Lower hDAT selectivity among benzofurans suggests similarity to methylenedioxymethamphetamine, entactogens with lower stimulant activity.

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KW - Benzofurans

KW - Cathinones

KW - New psychoactive substances

KW - Pharmacology

KW - Psychostimulant

KW - Transporter

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