Synthesis and monoamine transporter binding properties of 2beta-[3'-(substituted benzyl)isoxazol-5-yl]- and 2beta-[3'-methyl-4'-(substituted phenyl)isoxazol-5-yl]-3beta-(substituted phenyl)tropanes.
A series of 2beta-[3'-(substituted benzyl)isoxazol-5-yl]- and 2beta-[3'-methyl-4'-(substituted phenyl)isoxazol-5-yl]-3beta-(substituted phenyl)tropanes were prepared and evaluated for affinities at dopamine, serotonin, and norepinephrine transporters using competitive radioligand binding assays. The 2beta-[3'-(substituted benzyl)isoxazol-5-yl]-3beta-(substituted phenyl)tropanes (3a-h) showed high binding affinities for the dopamine transporter (DAT). The IC(50) values ranged from 5.9 to 22nM. On the other hand, the 2beta-[3'-methyl-4'-(substituted phenyl)isoxazol-5-yl]-3beta-(substituted phenyl)tropanes (4a-h), with IC(50) values ranging from 65 to 173nM, were approximately 3- to 25-fold less potent than the corresponding 2beta-[3'-(substituted benzyl)isoxazol]tropanes. All tested compounds were selective for the DAT relative to the norepinephrine transporter (NET) and serotonin transporter (5-HTT). 3Beta-(4-Methylphenyl)-2beta-[3'-(4-fluorobenzyl)isoxazol-5-yl]tropane (3b) with IC(50) of 5.9nM at the DAT and K(i)s of 454 and 113nM at the NET and 5-HTT, respectively, was the most potent and DAT-selective analog. Molecular modeling studies suggested that the rigid conformation of the isoxazole side chain in 4a-h might play an important role on their low DAT binding affinities.
Organic and Medicinal Chemistry, Research Triangle Institute, PO Box 12194, Research Triangle Park, NC 27709-2194, USA.
Chunyang
C
Jin
Hernán A
HA
Navarro
Kevin
K
Page
F Ivy
FI
Carroll
D000818:Animals; D001667:Binding, Competitive; D050483:Dopamine Plasma Membrane Transport Proteins; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D050484:Norepinephrine Plasma Membrane Transport Proteins; D050480:Plasma Membrane Neurotransmitter Transport Proteins / Q000378:metabolism*; D011869:Radioligand Assay; D050486:Serotonin Plasma Membrane Transport Proteins; D013329:Structure-Activity Relationship; D014326:Tropanes / Q000138:chemical synthesis* / Q000378:metabolism*
D050483:Dopamine Plasma Membrane Transport Proteins; D050484:Norepinephrine Plasma Membrane Transport Proteins; D050480:Plasma Membrane Neurotransmitter Transport Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; D014326:Tropanes