18085-03-5Relevant articles and documents
Development of a rationally designed, low abuse potential, biogenic amine releaser that suppresses cocaine self-administration
Rothman, Richard B.,Blough, Bruce E.,Woolverton, William L.,Anderson, Karen G.,Negus, S. Stevens,Mello, Nancy K.,Roth, Bryan L.,Baumann, Michael H.
, p. 1361 - 1369 (2005)
Convergent lines of evidence support a dual deficit model of stimulant withdrawal, where reductions in synaptic dopamine (DA) and 5-hydroxytryptamine (serotonin) (5-HT) contribute to dysphoria, drug craving, and relapse. Thus, we predicted that a nonamphetamine compound with substrate activity at DA and 5-HT transporters (i.e., a dual DA/5-HT releaser) would be an effective medication for treating stimulant addictions. Ideally, this type of medication would alleviate withdrawal symptoms, suppress cocaine self-administration, and lack side effects commonly associated with central nervous system stimulants. In the present work, more than 350 compounds were screened in vitro for activity as substrate-type releasing agents at DA, 5-HT, and norepinephrine transporters. These efforts identified PAL-287 (1-napthyl-2-aminopropane) as a nonamphetamine compound with potent substrate activity at biogenic amine transporters. In vivo microdialysis in rats demonstrated that PAL-287 (1-3 mg/kg i.v.) increased extracellular DA and 5-HT in frontal cortex, but effects on 5-HT were somewhat greater. PAL-287 induced substantially less locomotor stimulation than (+)-amphetamine, a drug that increases only extracellular DA. Administration of high-dose (+)-methamphetamine or (±)-3,4-methylenedioxymethamphetamine to rats produced long-lasting depletion of cortical 5-HT, whereas PAL-287 (18 mg/kg i.p. × 3) did not. PAL-287 displayed little or no reinforcing properties in rhesus monkeys trained to self-administer cocaine, yet PAL-287 produced a dose-dependent decrease in responding for cocaine when infused at a dose of 1.0 mg/kg/h. Collectively, the findings reported here demonstrate that nonamphetamine monoamine releasing agents such as PAL-287 might be promising candidate medications for the treatment of stimulant dependence.
Straightforward preparation of biologically active 1-aryl- and 1-heteroarylpropan-2-amines in enantioenriched form
Rodriguez-Mata, Maria,Gotor-Fernandez, Vicente,Gonzalez-Sabin, Javier,Rebolledo, Francisca,Gotor, Vicente
experimental part, p. 2274 - 2278 (2011/05/02)
Because of the importance of developing stereoselective syntheses for single enantiomers, a selected panel of racemic biologically active 1-aryl- and 1-heteroarylpropan-2-amines has been prepared, followed by a study of their behavior in enzymatic kinetic resolution (KR) processes. For this purpose, lipase B from Candida antarctica (CAL-B) proved to be an ideal biocatalyst allowing the preparation of the corresponding enantioenriched (R)-amides and (S)-amines by aminolysis reactions. Likewise, dynamic kinetic resolutions (DKR) have been successfully achieved combining the use of CAL-B and Shvo's catalyst. This research constitutes the first example of a lipase-catalyzed DKR process of β-substituted isopropylamines.
