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 transporters for the biogenic amines dopamine (DA), serotonin (5HT), and norepinephrine (NE) and release these neurotransmitters from neurons located in the peripheral and central nervous system. Using indatraline as a lead compound, we sought to develop a long-acting depot medication that would neutralize the deleterious effects of amphetamine-type stimulants. Our first efforts produced (+/-)-HY038, and its two stereoisomers, which are hydroxy-substituted analog of indatraline. The K(i) values for [(3)H]DA reuptake inhibition by (-)-HY038 and (+)-HY038 were 3.2 +/- 0.1 and 32 +/- 1 nM. Similar results were obtained for [(3)H]5HT reuptake inhibition. (-)-HY038 and (+)-HY038 were slightly less potent at inhibiting [(3)H]NE reuptake (K(i) values of 20 +/- 2 and 159 +/- 12 nM). Low doses of (-)-HY038 blunted the ability of AMPH to release [(3)H]DA by shifting the AMPH dose-response curve to the right in a dose-dependent manner. (-)-HY038 also inhibited the ability of (+)-methamphetamine and (+/-)-3,4-methylenedioxymethamphetamine ((+/-)-MDMA) to release [(3)H]DA. Low doses of (-)-HY038 blunted the ability of these stimulants to release [(3)H]NE and [(3)H]5HT by shifting their dose-response curves to the right in a manner similar to that seen for inhibition of [(3)H]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 side-effects of substrate-type stimulants.
Partilla
J S
JS
Clinical Psychopharmacology Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD 21224, USA.
Dersch
C M
CM
Yu
H
H
Rice
K C
KC
Rothman
R B
RB
D019969:Amphetamine-Related Disorders / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D000662:Amphetamines / Q000819:agonists*; D000818:Animals; D015306:Biogenic Monoamines / Q000378:metabolism; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D002352:Carrier Proteins / Q000187:drug effects / Q000378:metabolism; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D004298:Dopamine / Q000493:pharmacokinetics; D007189:Indans / Q000819:agonists* / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D008744:Methylamines / Q000819:agonists* / Q000378:metabolism; D014179:Neurotransmitter Uptake Inhibitors / Q000819:agonists* / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D014316:Tritium
D000662:Amphetamines; D015306:Biogenic Monoamines; D002352:Carrier Proteins; D000697:Central Nervous System Stimulants; C425384:HY 038; D007189:Indans; D008744:Methylamines; D014179:Neurotransmitter Uptake Inhibitors; D014316:Tritium; C418119:indatraline; D004298:Dopamine