Functional characterization of N-octyl 4-methylamphetamine variants and related bivalent compounds at the dopamine and serotonin transporters using Ca channels as sensors.

The early characterization of ligands at the dopamine and serotonin transporters, DAT and SERT, respectively, is important for drug discovery, forensic sciences, and drug abuse research. 4-Methyl amphetamine (4-MA) is a good example of an abused drug whose overdose can be fatal. It is a potent substrate at DAT and SERT where its simplest secondary amine (N-methyl 4-MA) retains substrate activity at them.

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

4-Methylamphetamine (4-MA) is an emerging drug of abuse that acts as a substrate at plasma membrane transporters for dopamine (DAT), norepinephrine (NET), and serotonin (SERT), thereby causing nonexocytotic release of monoamine transmitters via reverse transport. Prior studies by us showed that increasing the N-alkyl chain length of N-substituted 4-MA analogues converts 4-MA from a transportable substrate (i.e.

N-Alkylated Analogs of 4-Methylamphetamine (4-MA) Differentially Affect Monoamine Transporters and Abuse Liability.

Clandestine chemists synthesize novel stimulant drugs by exploiting structural templates known to target monoamine transporters for dopamine, norepinephrine, and serotonin (DAT, NET, and SERT, respectively). 4-Methylamphetamine (4-MA) is an emerging drug of abuse that interacts with transporters, but limited structure-activity data are available for its analogs. Here we employed uptake and release assays in rat brain synaptosomes, voltage-clamp current measurements in cells expressing transporters, and calcium flux assays in cells coexpressing transporters and calcium channels to study the effects of increasing N-alkyl chain length of 4-MA on interactions at DAT, NET, and SERT.

Retigabine holds KV7 channels open and stabilizes the resting potential.

The anticonvulsant Retigabine is a KV7 channel agonist used to treat hyperexcitability disorders in humans. Retigabine shifts the voltage dependence for activation of the heteromeric KV7.2/KV7.

Amphetamine activates calcium channels through dopamine transporter-mediated depolarization.

Amphetamine (AMPH) and its more potent enantiomer S(+)AMPH are psychostimulants used therapeutically to treat attention deficit hyperactivity disorder and have significant abuse liability. AMPH is a dopamine transporter (DAT) substrate that inhibits dopamine (DA) uptake and is implicated in DA release. Furthermore, AMPH activates ionic currents through DAT that modify cell excitability presumably by modulating voltage-gated channel activity.

Electrical coupling between the human serotonin transporter and voltage-gated Ca(2+) channels.

Monoamine transporters have been implicated in dopamine or serotonin release in response to abused drugs such as methamphetamine or ecstasy (MDMA). In addition, monoamine transporters show substrate-induced inward currents that may modulate excitability and Ca(2+) mobilization, which could also contribute to neurotransmitter release. How monoamine transporters modulate Ca(2+) permeability is currently unknown.