Discovery of a Novel Dopamine Transporter Inhibitor,
4-Hydroxy-1-methyl-4-(4-methylphenyl)-3-piperidyl 4-Methylphenyl Ketone, as a
Potential Cocaine Antagonist through 3D-Database Pharmacophore Searching.
Molecular Modeling, Structure−Activity Relationships, and Behavioral
Pharmacological Studies
posted on 2000-01-19, 00:00authored byShaomeng Wang, Sukumar Sakamuri, Istvan J. Enyedy, Alan P. Kozikowski, Olivier Deschaux, Bidhan C. Bandyopadhyay, Srihari R. Tella, Wahiduz A. Zaman, Kenneth M. Johnson
A novel, fairly potent dopamine transporter (DAT) inhibitor, 4-hydroxy-1-methyl-4-(4-methylphenyl)-3-piperidyl 4-methylphenyl ketone (3, Ki values of 492 and 360 nM in binding affinity
and inhibition of dopamine reuptake, respectively), with significant functional antagonism
against cocaine and a different in vitro pharmacological profile from cocaine at the three
transporter sites (dopamine, serotonin, and norepinephrine) was discovered through 3D-database pharmacophore searching. Through structure−activity relationships and molecular
modeling studies, we found that hydrophobicity and conformational preference are two
additional important parameters that determine affinity at the DAT site. Chemical modifications of the lead compound (3) led to a high affinity analogue (6, Ki values of 11 and 55 nM in
binding affinity and inhibition of dopamine reuptake, respectively). In behavioral pharmacological testing, 6 mimics partially the effect of cocaine in increasing locomotor activity in mice but
lacks cocaine-like discriminative stimulus effect in rats. Taken together, these data suggest
that 6 represents a promising lead for further evaluations as potential therapy for the treatment
of cocaine abuse.