Deconstructed Analogues of Bupropion Reveal Structural Requirements for Transporter Inhibition versus Substrate-Induced Neurotransmitter Release

Abstract

Bupropion (1), an α-aminophenone uptake inhibitor at plasma membrane transporters for dopamine (DAT) and norepinephrine (NET), is a widely prescribed antidepressant and smoking cessation aid. Cathinone (2), a structurally simpler α-aminophenone, is a substrate-type releasing agent at the same transporters and a recognized drug of abuse. Our goal was to identify the structural features of α-aminophenones that govern the mechanistic transition from uptake inhibition to substrate-induced release. Deconstructed analogues of 1 were synthesized and compared for their ability to interact with DAT, NET, and the serotonin transporter (SERT) using in vitro assay methods. Bulky amine substituents resulted in compounds that function as DAT uptake inhibitors but not release agents, whereas smaller amine substituents result in relatively nonselective releasing agents at DAT and NET. Our findings add to empirical evidence supporting distinct molecular determinants for α-aminophenone- (i.e., cathinone-) related agents acting as transporter inhibitors versus those acting as releasers.

Effects of N-Alkyl-4-Methylamphetamine Optical Isomers on Plasma Membrane Monoamine Transporters and Abuse-Related Behavior

“…In summary, the current study, coupled with out earlier investigations, 14,15 provides additional evidence that bulk around the terminal amine of phenylalkylamines such as amphetamine or cathinone (e.g. increasing chain length from NH to N-Me, to N-Et, to N- n -Pr, or to other bulky substituents as shown previously 14 ), and their optical isomers, dictate whether they will behave as MAT releasing agents or as MAT reuptake inhibitors.…”

“…We have previously found that tertiary amine analogs of synthetic cathinones behave as DAT reuptake inhibitors, but the present and related studies (e.g. 14 ) show that secondary amine analogs of amphetamine and cathinone can also play this role if their alkyl-length or bulk is increased. N-Alkyl substituted phenylalkylamine analogs, and optical isomers thereof, also have a role in MAT selectivity/function and abuse liability as shown here (and before 14,15 ).…”

“…increasing chain length from NH to N-Me, to N-Et, to N- n -Pr, or to other bulky substituents as shown previously 14 ), and their optical isomers, dictate whether they will behave as MAT releasing agents or as MAT reuptake inhibitors. It seems that the bulkier the N-substituent, the more likely the agent will act as a reuptake inhibitor at DAT.…”

“…14 ) show that secondary amine analogs of amphetamine and cathinone can also play this role if their alkyl-length or bulk is increased. N-Alkyl substituted phenylalkylamine analogs, and optical isomers thereof, also have a role in MAT selectivity/function and abuse liability as shown here (and before 14,15 ). Further investigation of N-alkyl amphetamine derivatives, and their corresponding β-keto analogs (i.e., synthetic cathinone analogs) is required.…”

“…e.g. 1,2,14 We recently investigated the effects of increasing the N-alkyl chain length on the transporter activity of 4-MA. 15 Specifically, we examined compounds 3–6 that introduced linear bulk on the amine of 4-MA in a homologous manner.…”