Brain disposition, metabolism and behavioral effects of the synthetic opioid AH-7921 in rats

Jacopo Lucchetti, Claudio M Marzo, Alice Passoni, Federico Moro, Angelo di Clemente, Renzo Bagnati, Luigi Cervo, Marco Gobbi

Research output: Contribution to journalArticle

Abstract

3,4-Dichloro-N-benzamide (AH-7921) is a cyclohexyl-methylbenzamide derivative with analgesic activity, whose abuse was associated with several fatal intoxications, included in Schedule I of UN Single Convention on Narcotic Drugs. We validated an HPLC-MS/MS method to investigate its brain disposition and metabolism after single and repeated injections; in parallel, we evaluated its central behavioral effects. After an intraperitoneal injection of 10 mg/kg, the analgesic effect appeared after 5 min and persisted up to 4 h; brain absorption was rapid (tmax 30 min) and large (brain-to-plasma ratio 16), with active concentration >700 ng/g. By high-resolution MS we identified several metabolites in plasma and brain, the most important being N-demethylated and N,N-didemethylated metabolites; they showed high brain permeability, although they probably do not contribute to the analgesic effect of the parent compound (brain tmax>2 h). Starting 2 h after treatment, the two metabolites showed higher plasma and brain concentrations than the parent molecule, which persisted much longer, and could be used to evaluate drug intake in human consumers. Tolerance was observed after seven daily doses, when the compound's analgesic effect was 14% lower than after the first dose; since brain concentrations did not decrease in parallel, the development of pharmacodynamic tolerance can be suggested. However, pharmacokinetic tolerance is also likely, as brought to light by the data after a dose challenge, given after a 48 h washout period from the 7th dose, showing a lower brain-to-plasma ratio. We also describe the rewarding effect of AH-7921 (conditioned place preference), suggesting a high risk of addiction in humans.

Original languageEnglish
Pages (from-to)51-62
Number of pages12
JournalNeuropharmacology
Volume133
DOIs
Publication statusPublished - May 1 2018

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Opioid Analgesics
Brain
Analgesics
AH 7921
United Nations
Narcotics
Intraperitoneal Injections
Pharmaceutical Preparations
Permeability
Appointments and Schedules
Pharmacokinetics
High Pressure Liquid Chromatography
Injections

Keywords

  • Analgesics, Opioid/chemical synthesis
  • Animals
  • Behavior, Animal/drug effects
  • Benzamides/blood
  • Brain/drug effects
  • Chromatography, High Pressure Liquid
  • Conditioning, Operant/drug effects
  • Dose-Response Relationship, Drug
  • Male
  • Metabolic Networks and Pathways/drug effects
  • Rats
  • Rats, Wistar
  • Tandem Mass Spectrometry
  • Time Factors

Cite this

Brain disposition, metabolism and behavioral effects of the synthetic opioid AH-7921 in rats. / Lucchetti, Jacopo; Marzo, Claudio M; Passoni, Alice; Moro, Federico; di Clemente, Angelo; Bagnati, Renzo; Cervo, Luigi; Gobbi, Marco.

In: Neuropharmacology, Vol. 133, 01.05.2018, p. 51-62.

Research output: Contribution to journalArticle

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T1 - Brain disposition, metabolism and behavioral effects of the synthetic opioid AH-7921 in rats

AU - Lucchetti, Jacopo

AU - Marzo, Claudio M

AU - Passoni, Alice

AU - Moro, Federico

AU - di Clemente, Angelo

AU - Bagnati, Renzo

AU - Cervo, Luigi

AU - Gobbi, Marco

N1 - Copyright © 2018 Elsevier Ltd. All rights reserved.

PY - 2018/5/1

Y1 - 2018/5/1

N2 - 3,4-Dichloro-N-benzamide (AH-7921) is a cyclohexyl-methylbenzamide derivative with analgesic activity, whose abuse was associated with several fatal intoxications, included in Schedule I of UN Single Convention on Narcotic Drugs. We validated an HPLC-MS/MS method to investigate its brain disposition and metabolism after single and repeated injections; in parallel, we evaluated its central behavioral effects. After an intraperitoneal injection of 10 mg/kg, the analgesic effect appeared after 5 min and persisted up to 4 h; brain absorption was rapid (tmax 30 min) and large (brain-to-plasma ratio 16), with active concentration >700 ng/g. By high-resolution MS we identified several metabolites in plasma and brain, the most important being N-demethylated and N,N-didemethylated metabolites; they showed high brain permeability, although they probably do not contribute to the analgesic effect of the parent compound (brain tmax>2 h). Starting 2 h after treatment, the two metabolites showed higher plasma and brain concentrations than the parent molecule, which persisted much longer, and could be used to evaluate drug intake in human consumers. Tolerance was observed after seven daily doses, when the compound's analgesic effect was 14% lower than after the first dose; since brain concentrations did not decrease in parallel, the development of pharmacodynamic tolerance can be suggested. However, pharmacokinetic tolerance is also likely, as brought to light by the data after a dose challenge, given after a 48 h washout period from the 7th dose, showing a lower brain-to-plasma ratio. We also describe the rewarding effect of AH-7921 (conditioned place preference), suggesting a high risk of addiction in humans.

AB - 3,4-Dichloro-N-benzamide (AH-7921) is a cyclohexyl-methylbenzamide derivative with analgesic activity, whose abuse was associated with several fatal intoxications, included in Schedule I of UN Single Convention on Narcotic Drugs. We validated an HPLC-MS/MS method to investigate its brain disposition and metabolism after single and repeated injections; in parallel, we evaluated its central behavioral effects. After an intraperitoneal injection of 10 mg/kg, the analgesic effect appeared after 5 min and persisted up to 4 h; brain absorption was rapid (tmax 30 min) and large (brain-to-plasma ratio 16), with active concentration >700 ng/g. By high-resolution MS we identified several metabolites in plasma and brain, the most important being N-demethylated and N,N-didemethylated metabolites; they showed high brain permeability, although they probably do not contribute to the analgesic effect of the parent compound (brain tmax>2 h). Starting 2 h after treatment, the two metabolites showed higher plasma and brain concentrations than the parent molecule, which persisted much longer, and could be used to evaluate drug intake in human consumers. Tolerance was observed after seven daily doses, when the compound's analgesic effect was 14% lower than after the first dose; since brain concentrations did not decrease in parallel, the development of pharmacodynamic tolerance can be suggested. However, pharmacokinetic tolerance is also likely, as brought to light by the data after a dose challenge, given after a 48 h washout period from the 7th dose, showing a lower brain-to-plasma ratio. We also describe the rewarding effect of AH-7921 (conditioned place preference), suggesting a high risk of addiction in humans.

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KW - Animals

KW - Behavior, Animal/drug effects

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KW - Chromatography, High Pressure Liquid

KW - Conditioning, Operant/drug effects

KW - Dose-Response Relationship, Drug

KW - Male

KW - Metabolic Networks and Pathways/drug effects

KW - Rats

KW - Rats, Wistar

KW - Tandem Mass Spectrometry

KW - Time Factors

U2 - 10.1016/j.neuropharm.2018.01.023

DO - 10.1016/j.neuropharm.2018.01.023

M3 - Article

VL - 133

SP - 51

EP - 62

JO - Neuropharmacology

JF - Neuropharmacology

SN - 0028-3908

ER -