Pharmacological and behavioral analysis of the effects of some bivalent ligand-based monoamine reuptake inhibitors.
Novel piperidine-based bivalent ligands were prepared in enantiomerically pure form and evaluated for their ability to inhibit reuptake of dopamine (DA), serotonin (5-HT), and norepinephrine (NE) into rat brain nerve endings (synaptosomes). In this study, we have succeeded in using (1) the length of the linking chain connecting the two piperidine-based monomer units and (2) the absolute configuration of the piperidine monomer as a means to tailor activity and selectivity at the three monoamine transporters tested. In this series, the bivalent ligand 16, comprised of two (+)-trans-piperidine units linked by a pentamethylene spacer, exhibits a combination of high DA transporter (DAT) and 5-HT transporter (SERT) activity (K(i) = 39 nM and 7 nM, respectively). Piperidine 16 is capable of reducing cocaine's locomotor effects in mice while not having any effect on locomotion when tested alone. Additionally, compound 16 (1-10 mg/kg) does not substitute for cocaine in drug discrimination studies in rats. However, the analogous bivalent ligand 15 comprised of two (-)-trans-piperidine units, which is SERT selective, was less effective in antagonizing cocaine's locomotor stimulant activity. The piperidine-based bivalent inhibitors described herein constitute a new class of monoamine reuptake inhibitors that exhibit varying levels of monoamine transporter activity and selectivity, and these ligands may serve as lead candidates in the discovery of new therapeutics to treat a range of neurological disorders including cocaine addiction.
Tamiz
A P
AP
Drug Discovery Program, Department of Neurology, Georgetown University Medical Center, 3900 Reservoir Road, NW, Washington, D.C. 20007-2197, USA.
Bandyopadhyay
B C
BC
Zhang
J
J
Flippen-Anderson
J L
JL
Zhang
M
M
Wang
C Z
CZ
Johnson
K M
KM
Tella
S
S
Kozikowski
A P
AP
D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D003042:Cocaine / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004193:Discrimination Learning / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins; D008024:Ligands; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D026901:Membrane Transport Proteins; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D009419:Nerve Tissue Proteins; D014179:Neurotransmitter Uptake Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009638:Norepinephrine / Q000378:metabolism; D050484:Norepinephrine Plasma Membrane Transport Proteins; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins; D013237:Stereoisomerism; D013239:Stereotyped Behavior / Q000187:drug effects; D013329:Structure-Activity Relationship; D027981:Symporters; D013574:Synaptosomes / Q000378:metabolism
C427232:1,5-bis((4-(4-chlorophenyl)-1-methylpiperidine-3-carbonyl)amino)pentane; D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D008024:Ligands; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D014179:Neurotransmitter Uptake Inhibitors; D050484:Norepinephrine Plasma Membrane Transport Proteins; D010880:Piperidines; D050486:Serotonin Plasma Membrane Transport Proteins; C493228:Slc6a2 protein, mouse; C493226:Slc6a2 protein, rat; C493215:Slc6a3 protein, mouse; C493216:Slc6a3 protein, rat; C493231:Slc6a4 protein, mouse; C493232:Slc6a4 protein, rat; D027981:Symporters; D012701:Serotonin; D003042:Cocaine; D004298:Dopamine; D009638:Norepinephrine