Neurochemical neutralization of amphetamine-type stimulants in rat brain by the indatraline analog (-)-HY038

Amphetamine-type stimulants are substrates for the proteins that serve as t ransporters for the biogenic amines dopamine (DA), serotonin (5HT), and nor epinephrine (NE) and release these neurotransmitters from neurons located i n the peripheral and central nervous system. Using indatraline as a lead co mpound, we sought to develop a long-acting depot medication that would neut ralize the deleterious effects of amphetamine-type stimulants. our first ef forts produced (+/-)-HY038, and its two stereoisomers, which are hydroxy-su bstituted analog of indatraline. The K-i values for [H-3]DA reuptake inhibi tion by (-)-HY038 and (+)-HY038 were 3.2 +/- 0.1 and 32 +/- 1 nM. Similar r esults were obtained for [H-3]5HT reuptake inhibition. (-)-HY038 and (+)-HY 038 were slightly less potent at inhibiting [H-3]NE reuptake (K-i values of 20 +/- 2 and 159 +/- 12 nM), Low doses of (-)-HY038 blunted the ability of AMPH to release [H-3]DA by shifting the AMPH dose-response curve to the ri ght in a dose-dependent manner. (-)-HY038 also inhibited the ability of (+) -methamphetamine and (+/-)-3,4-methylenedioxymethamphetamine ((+/-)-MDMA) t o release [H-3]DA. Low doses of (-)-HY038 blunted the ability of these stim ulants to release [H-3]NE and [H-3]5HT by shifting their dose-response! cur ves to the right in a manner similar to that seen for inhibition of [H-3]DA release, These data indicate that (-)-HY038 inhibits the ability of AMPH, (+)-methamphetamine and (+/-)-MDMA to release DA, NE, and 5HT and therefore might have the potential to neutralize the neurotoxic and cardiovascular s ide-effects of substrate-type stimulants. (C) 2001 Elsevier Science Inc.