PMID- 38272669
OWN - NLM
STAT- Publisher
LR  - 20240125
IS  - 1521-0103 (Electronic)
IS  - 0022-3565 (Linking)
DP  - 2024 Jan 25
TI  - Novel Benzofuran Derivatives Induce Monoamine Release and Substitute for the 
      Discriminative Stimulus Effects of 3,4-Methylenedioxymethamphetamine.
LID - JPET-AR-2023-001837 [pii]
LID - 10.1124/jpet.123.001837 [doi]
AB  - 3,4-Methylenedioxymethamphetamine (MDMA) has shown efficacy as a medication 
      adjunct for treating post-traumatic stress disorder (PTSD). However, MDMA is also 
      used in non-medical contexts that pose risk for cardiovascular and neurological 
      complications. It is well established that MDMA exerts its effects by stimulating 
      transporter-mediated release of the monoamines, 5‑hydroxytryptamine (5-HT), 
      norepinephrine, and dopamine. Current research efforts are aimed at developing 
      MDMA-like monoamine releasers with better efficacy and safety profiles. To this 
      end, we investigated neurochemical and behavioral effects of novel analogs of the 
      designer drug, 5-(2-methylaminopropyl)benzofuran (5-MAPB). We used in vitro 
      transporter assays in rat brain synaptosomes to examine transmitter uptake 
      inhibition and releasing properties for enantiomers of 
      5-(2-methylaminobutyl)benzofuran (5-MABB) and 6-(2-methylaminobutyl)benzofuran 
      (6-MABB) as compared to MDMA. We then tested these same compounds in male 
      Sprague-Dawley rats trained to discriminate MDMA (1.5 mg/kg) from saline. In 
      vitro results revealed that S isomers of 5- and 6-MABB are efficacious releasing 
      agents at transporters for 5-HT (SERT), norepinephrine (NET), and dopamine (DAT). 
      By contrast, R isomers are efficacious releasers at SERT, partial releasers at 
      NET, but lack releasing activity at DAT. In vivo results showed that all 
      compounds produce dose-dependent increases in MDMA-lever responding and full 
      substitution at the highest dose tested. The diminished NET and DAT releasing 
      activities for R isomers of 5- and 6-MABB are associated with reduced potency for 
      inducing behavioral effects. Collectively, these findings indicate that the 
      aminoalkyl benzofuran scaffold may be a viable template for developing compounds 
      with MDMA-like properties. Significance Statement Despite the clinical utility of 
      MDMA, the drug is associated with certain cardiovascular risks and metabolic side 
      effects. Developing a therapeutic alternative with MDMA-like monoamine releasing 
      activity is of interest. Our in vitro and in vivo findings indicate that the 
      aminoalkyl benzofuran scaffold may be useful for developing compounds with 
      MDMA-like properties.
CI  - U.S. Government Work not Protected by U.S. Copyright.
FAU - Johnson, Candace B
AU  - Johnson CB
AD  - Psychology, Western Michigan University, United States.
FAU - Walther, Donna
AU  - Walther D
AD  - Designer Drug Research Unit, National Institute on Drug Abuse (NIDA), United 
      States.
FAU - Baggott, Matthew J
AU  - Baggott MJ
AD  - Tactogen, United States mbaumann@intra.nida.nih.gov.
FAU - Baker, Lisa E
AU  - Baker LE
AD  - Western Michigan University, United States.
FAU - Baumann, Michael H
AU  - Baumann MH
AD  - Designer Drug Research Unit, National Institute on Drug Abuse (NIDA), United 
      States mbaumann@intra.nida.nih.gov.
LA  - eng
PT  - Journal Article
DEP - 20240125
PL  - United States
TA  - J Pharmacol Exp Ther
JT  - The Journal of pharmacology and experimental therapeutics
JID - 0376362
SB  - IM
OTO - NOTNLM
OT  - Dopamine
OT  - Serotonin
OT  - drug discrimination
EDAT- 2024/01/26 00:43
MHDA- 2024/01/26 00:43
CRDT- 2024/01/25 21:40
PHST- 2024/01/18 00:00 [accepted]
PHST- 2023/07/13 00:00 [received]
PHST- 2023/12/21 00:00 [revised]
PHST- 2024/01/26 00:43 [medline]
PHST- 2024/01/26 00:43 [pubmed]
PHST- 2024/01/25 21:40 [entrez]
AID - jpet.123.001837 [pii]
AID - 10.1124/jpet.123.001837 [doi]
PST - aheadofprint
SO  - J Pharmacol Exp Ther. 2024 Jan 25:JPET-AR-2023-001837. doi: 
      10.1124/jpet.123.001837.