2,3-Disubstituted quinuclidines as a novel class of dopamine transporter inhibitors.
There 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 microM 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.
Sakamuri
Sukumar
S
Department of Neurology, Georgetown University Medical Center, 3900 Reservoir Rd., Washington, DC 20007, USA.
Enyedy
Istvan J
IJ
Zaman
Wahiduz A
WA
Tella
Srihari R
SR
Kozikowski
Alan P
AP
Flippen-Anderson
Judith L
JL
Farkas
Tivadar
T
Johnson
Kenneth M
KM
Wang
Shaomeng
S
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001667:Binding, Competitive / Q000187:drug effects; D003042:Cocaine / Q000494:pharmacology; D004192:Discrimination, Psychological / Q000187:drug effects; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004347:Drug Interactions; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D008454:Mazindol / Q000378:metabolism; D008562:Membrane Glycoproteins; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins / Q000037:antagonists & inhibitors*; D051379:Mice; D008958:Models, Molecular; D009043:Motor Activity / Q000187:drug effects; D009419:Nerve Tissue Proteins; D011485:Protein Binding; D011487:Protein Conformation; D011812:Quinuclidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism
D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D007202:Indicators and Reagents; D008562:Membrane Glycoproteins; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D011812:Quinuclidines; C493215:Slc6a3 protein, mouse; C493216:Slc6a3 protein, rat; D008454:Mazindol; D003042:Cocaine