Structure-Activity Relationships for a Recently Controlled Synthetic Cathinone Dopamine Transporter Reuptake Inhibitor: α-Pyrrolidinohexiophenone (α-PHP)

ACS Chem Neurosci. 2023 Jul 19;14(14):2527-2536. doi: 10.1021/acschemneuro.3c00156. Epub 2023 Jul 5.

Abstract

α-Pyrrolidinohexiophenone (α-PHP) is the one-carbon unit α-extended homolog of the better-known and widely abused synthetic cathinone central stimulant α-PVP ("flakka"); both are now U.S. Schedule I controlled substances. Structurally, α-PVP and α-PHP possess a common terminal N-pyrrolidine moiety and differ only with respect to the length of their α-alkyl chain. Using a synaptosomal assay, we previously reported that α-PHP is at least as potent as α-PVP as a dopamine transporter (DAT) reuptake inhibitor. A systematic structure-activity study of synthetic cathinones (e.g., α-PHP) as DAT reuptake inhibitors (i.e., transport blockers), a mechanism thought responsible for their abuse liability, has yet to be conducted. Here, we examined a series of 4-substituted α-PHP analogues and found that, with one exception, all behaved as relatively (28- to >300-fold) selective DAT versus serotonin transporter (SERT) reuptake inhibitors with DAT inhibition potencies of most falling within a very narrow (i.e., <3-fold) range. The 4-CF3 analogue of α-PHP was a confirmed "outlier" in that it was at least 80-fold less potent than the other analogues and displayed reduced (i.e., no) DAT vs SERT selectivity. Consideration of various physicochemical properties of the CF3 group, relative to that of the other substituents involved here, provided relatively little insight. Unlike with DAT-releasing agents, as previously reported by us, a QSAR study was precluded because of the limited range of empirical results (with the exception of the 4-CF3 analogue) for DAT reuptake inhibition.

Keywords: DAT reuptake inhibition; SERT reuptake inhibition; cathinone analogues; dopamine transporter; drug abuse; serotonin transporter; α-PVP.

Publication types

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

MeSH terms

  • Dopamine Plasma Membrane Transport Proteins* / metabolism
  • Dopamine Uptake Inhibitors / chemistry
  • Dopamine Uptake Inhibitors / pharmacology
  • Pyrrolidines / chemistry
  • Pyrrolidines / pharmacology
  • Selective Serotonin Reuptake Inhibitors
  • Serotonin Plasma Membrane Transport Proteins
  • Structure-Activity Relationship
  • Synthetic Cathinone*

Substances

  • alpha-pyrrolidinohexanophenone
  • alpha-pyrrolidinohexiophenone
  • 1-phenyl-2-(1-pyrrolidinyl)-1-pentanone
  • Synthetic Cathinone
  • Dopamine Plasma Membrane Transport Proteins
  • Pyrrolidines
  • Dopamine Uptake Inhibitors
  • Serotonin Plasma Membrane Transport Proteins
  • Selective Serotonin Reuptake Inhibitors