Development of 3-phenyltropane analogues with high affinity for the dopamine and serotonin transporters and low affinity for the norepinephrine transporter.
Previous studies showed that the mixed monoamine transporter inhibitor (6, RTI-112) reduced cocaine self-administration at a high level of serotonin transporter (5-HTT) occupancy with no detectable dopamine transporter (DAT) occupancy. In this study, a series of 3beta-(substituted phenyl)tropane-2beta-carboxylic acid methyl esters (7a-g), 3beta-(4-methoxyphenyl)tropane-2beta-carboxylic acid esters (8a-j), and 3beta-(4-methoxyphenyl)-2beta-[3-(4'-methylphenyl)isoxazol-5-yl]tropane (9) were synthesized and evaluated for their monoamine transporter binding affinities to identify potent and selective compounds for both the DAT and 5-HTT relative to the norepinephrine transporter (NET). A number of compounds showed high binding affinities for both the DAT and 5-HTT and low affinity for the NET. 3Beta-(4-methoxyphenyl)tropane-2beta-carboxylic acid 2-(3-iodo-4-aminophenyl)ethyl ester (8i) with an IC(50) value of 2.5 nM for the DAT and K(i) values of 3.5 and 2040 nM for the 5-HTT and NET, respectively, is the most potent and selective compound for the DAT and 5-HTT relative to the NET in this study.
Jin
Chunyang
C
Center for Organic and Medicinal Chemistry, Research Triangle Institute, Research Triangle Park, North Carolina 27709-2194, USA.
Navarro
Hernán A
HA
Carroll
F Ivy
FI
D002626:Chemistry, Pharmaceutical / Q000379:methods*; D003042:Cocaine / Q000031:analogs & derivatives* / Q000737:chemistry; D050483:Dopamine Plasma Membrane Transport Proteins / Q000737:chemistry*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008956:Models, Chemical; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000737:chemistry* / Q000502:physiology*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013696:Temperature; D014326:Tropanes / Q000737:chemistry*
D050483:Dopamine Plasma Membrane Transport Proteins; D050484:Norepinephrine Plasma Membrane Transport Proteins; C432869:RTI 112; D050486:Serotonin Plasma Membrane Transport Proteins; D014326:Tropanes; C021278:troparil; D003042:Cocaine