Pharmacophore-based discovery of 3,4-disubstituted pyrrolidines as a novel class of monoamine transporter inhibitors.
3,4-Disubstituted pyrrolidines were discovered as a novel class of monoamine transporter inhibitors through 3-D database pharmacophore searching using a new pharmacophore model. The most potent analogue 12 has Ki values of 0.084 microM in [3H]mazindol binding, 0.20, 0.23, and 0.031 microM in inhibition of dopamine (DA), serotonin (SER), and norepinephrine (NE) reuptake, respectively. Functional antagonism testing in vitro showed that 11 and 12 are weak cocaine antagonists.
Enyedy
I J
IJ
Department of Oncology, Georgetown University Medical Center, Washington, DC 20007, USA.
Zaman
W A
WA
Sakamuri
S
S
Kozikowski
A P
AP
Johnson
K M
KM
Wang
S
S
D015306:Biogenic Monoamines / Q000378:metabolism*; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D003042:Cocaine / Q000037:antagonists & inhibitors; D018765:Dopamine Uptake Inhibitors / Q000037:antagonists & inhibitors / Q000378:metabolism; D008454:Mazindol / Q000378:metabolism; D014179:Neurotransmitter Uptake Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship
D015306:Biogenic Monoamines; D002352:Carrier Proteins; D018765:Dopamine Uptake Inhibitors; D014179:Neurotransmitter Uptake Inhibitors; D011759:Pyrrolidines; D008454:Mazindol; D003042:Cocaine