Synthesis and structure-activity relationship of 3beta-(4-alkylthio, -methylsulfinyl, and -methylsulfonylphenyl)tropane and 3beta-(4-alkylthiophenyl)nortropane derivatives for monoamine transporters.
Early studies led to the identification of 3beta-(4-methoxyphenyl)tropane-2beta-carboxylic acid methyl ester (5) with high affinity at the DAT (IC(50)=6.5nM) and 5-HTT (K(i)=4.3nM), while having much less affinity at the NET (K(i)=1110nM). In the present study, we replaced the 4'-methoxy group of the 3beta-phenyl ring with a bioisosteric 4'-methylthio group to give 7a. We also synthesized a number of 3beta-(4-alkylthiophenyl)tropanes 7b-e, 3beta-(4-methylsulfinylphenyl) and 3beta-(4-methylsulfonylphenyl)tropane analogues 7f-h as well as the 3beta-(4-alkylthiophenyl)nortropane derivatives 8-11 to further characterize the structure-activity relationship of this type of compound for binding at monoamine transporters. With exception of the 4'-methylsulfonyl analogue 7h, all the tested compounds possessed high binding affinities at the 5-HTT. The K(i) values ranged from 0.19nM to 49nM. The 3beta-(4-methylthiophenyl)tropane 7a and its N-(3-fluoropropyl) analogue 9a and N-allyl analogue 10a are the most selective compounds for the 5-HTT over the NET (NET/5-HTT=314-364) in the series. However, none of the compounds showed selectivity similar to 5 for both the DAT and 5-HTT relative to the NET. This study provided useful SAR information for rational design of potent and selective monoamine transporter inhibitors.
Jin
Chunyang
C
Organic and Medicinal Chemistry, Research Triangle Institute, PO Box 12194, Research Triangle Park, NC 27709-2194, USA. cjin@rti.org
Navarro
Hernán A
HA
Ivy Carroll
F
F
D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism*; D006801:Humans; D015394:Molecular Structure; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000378:metabolism*; D009662:Nortropanes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014326:Tropanes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
D050483:Dopamine Plasma Membrane Transport Proteins; D050484:Norepinephrine Plasma Membrane Transport Proteins; D009662:Nortropanes; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; D014326:Tropanes