Design, synthesis, and monoamine transporter binding site affinities of methoxy derivatives of indatraline.
A series of methoxy-containing derivatives of indatraline 13a-f and 17 were synthesized, and their binding affinities for the dopamine, serotonin, and norepinephrine transporter binding sites were determined. Introduction of a methoxy group to indatraline affected its affinity and selectivity greatly. Except for the 4-methoxy derivative 13a,which had the same high affinity at the dopamine transporter binding site as indatraline, the other methoxy-containing analogues (13b-f and 17) exhibited lower affinity than indatraline for the three transporter binding sites. However, some of the analogues were more selective than indatraline, and the 6-methoxy derivative 13c displayed the highest affinity for both the serotonin and norepinephrine transporters. This compound retained reasonable affinity for the dopamine transporter and is a promising template for the development of a long-acting inhibitor of monoamine transporters. Such inhibitors have potential as medications for treatment, as a substitution medication, or for prevention of the abuse of methamphetamine-like stimulants.
Gu
X H
XH
Laboratory of Medicinal Chemistry, Building 8, Room B1-23, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-0815, USA.
Yu
H
H
Jacobson
A E
AE
Rothman
R B
RB
Dersch
C M
CM
George
C
C
Flippen-Anderson
J L
JL
Rice
K C
KC
D000818:Animals; D001667:Binding, Competitive; D002352:Carrier Proteins / Q000378:metabolism*; D018360:Crystallography, X-Ray; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins; D015195:Drug Design; D007189:Indans / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism*; D026901:Membrane Transport Proteins; D008744:Methylamines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D009419:Nerve Tissue Proteins; D014179:Neurotransmitter Uptake Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism*; D050484:Norepinephrine Plasma Membrane Transport Proteins; D011869:Radioligand Assay; D012701:Serotonin / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins; D013329:Structure-Activity Relationship; D027981:Symporters
C418120:(3-(3,4-dichlorophenyl)-4-methoxyindan-1-yl)methylamine; D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D007189:Indans; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D008744:Methylamines; D009419:Nerve Tissue Proteins; D014179:Neurotransmitter Uptake Inhibitors; D050484:Norepinephrine Plasma Membrane Transport Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; D027981:Symporters; D012701:Serotonin; C418119:indatraline; D004298:Dopamine; D009638:Norepinephrine