High affinity hydroxypiperidine analogues of 4-(2-benzhydryloxyethyl)-1-(4-fluorobenzyl)piperidine for the dopamine transporter: stereospecific interactions in vitro and in vivo.
In our effort to develop high-affinity ligands for the dopamine transporter which might find potential use as cocaine medication, a polar hydroxy substituent was introduced into the piperidine ring of one of our disubstituted lead analogues derived from 1-[2-(diphenylmethoxy)-ethyl]-4-(3-phenylpropyl)piperazine (GBR 12935). Both cis- and trans-3-hydroxy derivatives were synthesized and the racemic trans isomer, (+/-)-5, was further resolved into two enantiomers. Newly synthesized compounds were characterized for their binding affinity at the dopamine, serotonin, and norepinephrine transporter systems in rat brain. The two enantiomers (+)-5 and (-)-5 exhibited marked differential affinities at the dopamine transporter with (+)-5 being 122-fold more potent than (-)-5 in inhibiting radiolabeled cocaine analogue binding (IC(50); 0.46 vs 56.7 nM) and 9-fold more active for inhibiting dopamine uptake (IC(50); 4.05 vs 38.0 nM). Furthermore, the most active (+)-5 was 22-fold more potent at the dopamine transporter compared to the standard GBR 12909. Absolute configuration of one of the enantiomers was determined unambiguously by X-ray structural analysis. In in vivo locomotor activity studies, the enantiomer (+)-5 and the racemic (+/-)-5, but not (-)-5, exhibited stimulant activity with a long duration of effect. All three compounds, (+)-5, (-)-5, and (+/-)-5, within the dose range tested, partially (50%) but incompletely (80%) produced cocaine-like responses in mice trained to discriminate 10 mg/kg ip cocaine from vehicle. Compound (-)-5 was distinctive in this regard in that, unlike (+)-5 and (+/-)-5, it did not affect locomotor activity yet, but similar to them, was able to engender (albeit incompletely) cocaine-like responses.
Ghorai
Sujit K
SK
Wayne State University, Department of Pharmaceutical Sciences, Detroit, Michigan 48202, USA.
Cook
Charles
C
Davis
Matthew
M
Venkataraman
Sylesh K
SK
George
Clifford
C
Beardsley
Patrick M
PM
Reith
Maarten E A
ME
Dutta
Aloke K
AK
D000818:Animals; D001559:Benzhydryl Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002352:Carrier Proteins / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D003042:Cocaine / Q000494:pharmacology; D003342:Corpus Striatum / Q000378:metabolism; D018360:Crystallography, X-Ray; D004193:Discrimination Learning / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D008024:Ligands; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000378:metabolism*; D051379:Mice; D015394:Molecular Structure; D009043:Motor Activity / Q000187:drug effects; D009419:Nerve Tissue Proteins; D050484:Norepinephrine Plasma Membrane Transport Proteins; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D050486:Serotonin Plasma Membrane Transport Proteins; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D027981:Symporters / Q000378:metabolism
C473481:4-(2-benzhydryloxyethyl)-1-(4-fluorobenzyl)piperidin-3-ol; D001559:Benzhydryl Compounds; D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D008024:Ligands; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D050484:Norepinephrine Plasma Membrane Transport Proteins; D010880:Piperidines; D050486:Serotonin Plasma Membrane Transport Proteins; C493228:Slc6a2 protein, mouse; C493226:Slc6a2 protein, rat; C493231:Slc6a4 protein, mouse; C493232:Slc6a4 protein, rat; D027981:Symporters; D003042:Cocaine; D004298:Dopamine