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Trifluoromethyl ring‐substituted methcathinone analogs: activity at monoamine uptake transporters
Author(s) -
Cozzi Nicholas V.,
Daley Paul F.,
Evans Darin L.,
Partilla John S.,
Rothman Richard B.,
Ruoho Arnold E.,
Baumann Michael H.
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.1083.1
Subject(s) - chemistry , norepinephrine transporter , pharmacology , dopamine transporter , monoamine neurotransmitter , dopamine , serotonin , transporter , serotonin transporter , stereochemistry , biochemistry , medicine , biology , receptor , gene
The psychostimulant effects of methcathinone result from inhibition of uptake and promotion of release of biogenic amines via the uptake transporters for serotonin (SERT), norepinephrine (NET), and dopamine (DAT). To explore the influence of chemical structure on activity at these transporters, we synthesized trifluoromethyl (CF 3 ) positional analogs of methcathinone with a CF 3 substituent at the 2‐, 3‐, or 4‐position of the phenyl ring. We tested these compounds for their abilities to inhibit [ 3 H]5‐HT (SERT) or [ 3 H]NE (NET) uptake, and as [ 3 H]5‐HT (SERT) or [ 3 H]MPP + (NET, DAT) releasing agents. At SERT, the 3‐CF 3 and 4‐CF 3 analogs were at least 10‐fold more potent than methcathinone itself as uptake inhibitors and releasers, but the 2‐CF 3 analog was both a poor uptake inhibitor and a weak releaser. At NET, on the other hand, all the CF 3 ‐methcathinone analogs were less potent than methcathinone as uptake inhibitors and releasers, with IC 50 and EC 50 values in the low μM range. The CF 3 derivatives were also less potent (30‐ to 400‐fold) than methcathinone as [ 3 H]MPP + releasers at DAT. These results support the hypothesis that substitutions at the 3‐ or 4‐positions of phenylalkylamines enhance activity at SERT and also suggest a structural approach (2‐substitution) for creating compounds that are selective for catecholamine transporters versus serotonin transporters. Support: DA017675 (NVC) and IRP, NIDA, NIH.