2,3-Disubstituted quinuclidines as a novel class
of dopamine transporter inhibitors
by
Sakamuri S, Enyedy IJ, Zaman WA, Tella SR,
Kozikowski AP, Flippen-Anderson JL, Farkas T, Johnson KM, Wang S.
Department of Neurology, Georgetown University Medical Center,
3900 Reservoir Rd., DC 20007, Washington, USA
Bioorg Med Chem 2003 Mar;11(6):1123-1136
ABSTRACTThere is considerable interest in developing dopamine transporter (DAT) inhibitors as potential therapies for the treatment of cocaine abuse. We report herein our pharmacophore-based discovery and molecular modeling-assisted rational design of 2,3-disubstituted quinuclidines as potent DAT inhibitors with a novel chemical scaffold. Through 3-D-database pharmacophore searching, compound 12 was identified as a very weak DAT inhibitor with K(i) values of 7.3 and 8.9 &mgr;M in [3H]mazindol binding and in inhibition of dopamine reuptake, respectively. Molecular modeling-assisted rational design and chemical modifications led to identification of potent analogues (-)-29 and 34 with K(i) values of 14 and 32 nM for both compounds in binding affinity and inhibition of dopamine reuptake, respectively. Behavioral pharmacological evaluations in rodents showed that 34 has a profile very different from cocaine. While 34 is substantially more potent than cocaine as a DAT inhibitor, it is approximately four times less potent than cocaine in mimicking the discriminative stimulus properties of cocaine in rat. On the other hand, 34 (3-30 mg/kg) lacks either the locomotor stimulant or stereotypic properties of cocaine in mice. Importantly, 34 blocks locomotor stimulant activity induced by 20 mg/kg cocaine in mice, with an estimated ED(50) of 19 mg/kg. Taken together, our data suggest that 34 represents a class of potent DAT inhibitors with a novel chemical scaffold and a behavioral pharmacological profile different from that of cocaine in rodents. Thus, 34 may serve as a novel lead compound in the ultimate development of therapeutic entities for cocaine abuse and/or addiction.D1
Cocaine substitutes
The pleasure centres
The nucleus accumbens
Dopamine/D1receptors
Dopamine/D2 receptors
Dopamine/D3 receptors
Dopamine/D4 receptors
Dopamine efflux and abused drugs01 02 03 04 05 06 07 08 09 10 11 12
13 14 15 16 17 18 19 20 21 22 23 24
Refs
HOME
HedWeb
cannabis-marijuana.com
Future Opioids
BLTC Research
Wirehead Hedonism
Paradise-Engineering
Utopian Pharmacology
The Hedonistic Imperative
When Is It Best to Take Crack Cocaine?
The Good Drug Guide
The Responsible Parent's Guide To
Healthy Mood Boosters For All The Family
