Discovery of a Novel Dopamine Transporter Inhibitor, 4-Hydroxy-1-methyl-4-(4-methylphenyl)-3-piperidyl 4-Methylphenyl Ketone, as a Potential Cocaine Antagonist through 3D-Database Pharmacophore Searching. Molecular Modeling, Structure−Activity Relationships, and Behavioral Pharmacological Studies

• Published in: Journal of medicinal chemistry Vol. 43; no. 3; pp. 351 - 360
• Main Authors: Wang, Shaomeng, Sakamuri, Sukumar, Enyedy, Istvan J, Kozikowski, Alan P, Deschaux, Olivier, Bandyopadhyay, Bidhan C, Tella, Srihari R, Zaman, Wahiduz A, Johnson, Kenneth M
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 10.02.2000; Amer Chemical Soc
• Subjects: Animals; Biological and medical sciences; Carrier Proteins - antagonists & inhibitors; Catecholaminergic system; Caudate Nucleus - metabolism; Chemistry, Medicinal; Cocaine - antagonists & inhibitors; Corpus Striatum - metabolism; Corpus Striatum - ultrastructure; Databases, Factual; Dopamine - metabolism; Dopamine Plasma Membrane Transport Proteins; Dopamine Uptake Inhibitors - chemical synthesis; Dopamine Uptake Inhibitors - chemistry; Dopamine Uptake Inhibitors - metabolism; Dopamine Uptake Inhibitors - pharmacology; Drug addictions; In Vitro Techniques; Life Sciences & Biomedicine; Medical sciences; Membrane Glycoproteins; Membrane Transport Proteins; Mice; Models, Molecular; Motor Activity - drug effects; Nerve Tissue Proteins; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Piperidines - chemical synthesis; Piperidines - chemistry; Piperidines - metabolism; Piperidines - pharmacology; Rats; Science & Technology; Structure-Activity Relationship; Synaptosomes - metabolism; Toxicology; ACID METHYL-ESTERS; LIGAND-BINDING; 3D DATABASE; ANALOGS; RECOGNITION SITES; HIGH-AFFINITY; DRUG DESIGN; CONFORMATIONAL-ANALYSIS; REUPTAKE BLOCKERS; SELECTIVITY; Replacement therapy; Rat; Central nervous system; Reuptake inhibitor; Modeling; Structure activity relation; Membrane transport; Chlorine Organic compounds; Tertiary alcohol; Molecular model; Piperidine derivatives; Inhibition; Chemical synthesis; Carrier protein; Aminoalcohol; Dopamine; Rodentia; Benzene derivatives; In vitro; In vivo; Locomotion; Vertebrata; Mammalia; Aminoketone; Mouse; Animal; Cocaine; Brain (vertebrata)
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm990516x

A novel, fairly potent dopamine transporter (DAT) inhibitor, 4-hydroxy-1-methyl-4-(4-methylphenyl)-3-piperidyl 4-methylphenyl ketone (3, K i values of 492 and 360 nM in binding affinity and inhibition of dopamine reuptake, respectively), with significant functional antagonism against cocaine and a different in vitro pharmacological profile from cocaine at the three transporter sites (dopamine, serotonin, and norepinephrine) was discovered through 3D-database pharmacophore searching. Through structure−activity relationships and molecular modeling studies, we found that hydrophobicity and conformational preference are two additional important parameters that determine affinity at the DAT site. Chemical modifications of the lead compound (3) led to a high affinity analogue (6, K i values of 11 and 55 nM in binding affinity and inhibition of dopamine reuptake, respectively). In behavioral pharmacological testing, 6 mimics partially the effect of cocaine in increasing locomotor activity in mice but lacks cocaine-like discriminative stimulus effect in rats. Taken together, these data suggest that 6 represents a promising lead for further evaluations as potential therapy for the treatment of cocaine abuse.