High Affinity Hydroxypiperidine Analogues of 4-(2-Benzhydryloxyethyl)-1-(4-fluorobenzyl)piperidine for the Dopamine Transporter:  Stereospecific Interactions in Vitro and in Vivo

• Published in: Journal of medicinal chemistry 2003-03, Vol.46 (7), p.1220-1228
• Main Authors: Ghorai, Sujit K, Cook, Charles, Davis, Matthew, Venkataraman, Sylesh K, George, Clifford, Beardsley, Patrick M, Reith, Maarten E. A, Dutta, Aloke K
• Format: Article
• Language: English
• Subjects: Animals; Benzhydryl Compounds - chemical synthesis; Benzhydryl Compounds - chemistry; Benzhydryl Compounds - pharmacology; Biological and medical sciences; Carrier Proteins - metabolism; Catecholaminergic system; Cerebral Cortex - metabolism; Cocaine - pharmacology; Corpus Striatum - metabolism; Crystallography, X-Ray; Discrimination Learning - drug effects; Dopamine - metabolism; Dopamine Plasma Membrane Transport Proteins; Dopamine Uptake Inhibitors - pharmacology; In Vitro Techniques; Ligands; Male; Medical sciences; Membrane Glycoproteins - metabolism; Membrane Transport Proteins - metabolism; Mice; Molecular Structure; Motor Activity - drug effects; Nerve Tissue Proteins; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Norepinephrine Plasma Membrane Transport Proteins; Pharmacology. Drug treatments; Piperidines - chemical synthesis; Piperidines - chemistry; Piperidines - pharmacology; Radioligand Assay; Rats; Serotonin Plasma Membrane Transport Proteins; Stereoisomerism; Structure-Activity Relationship; Symporters - metabolism
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm020275k

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 (IC50; 0.46 vs 56.7 nM) and 9-fold more active for inhibiting dopamine uptake (IC50; 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.