2,3-Disubstituted quinuclidines as a novel class of dopamine transporter inhibitors

Autor: Sukumar Sakamuri, Alan P. Kozikowski, Kenneth M. Johnson, Srihari R. Tella, Istvan J. Enyedy, Shaomeng Wang, Wahiduz A. Zaman, Tivadar Farkas, Judith L. Flippen-Anderson
Rok vydání: 2003
Předmět:
Models
Molecular
Quinuclidines
Magnetic Resonance Spectroscopy
Protein Conformation
medicine.medical_treatment
Clinical Biochemistry
Drug Evaluation
Preclinical
Pharmaceutical Science
Nerve Tissue Proteins
Motor Activity
Pharmacology
Binding
Competitive
Biochemistry
Reuptake
Mice
Structure-Activity Relationship
chemistry.chemical_compound
Discrimination
Psychological
Cocaine
Dopamine Uptake Inhibitors
Dopamine
Membrane Transport Modulators
Drug Discovery
medicine
Animals
Drug Interactions
Neurotransmitter
Molecular Biology
Dopamine transporter
Dopamine Plasma Membrane Transport Proteins
Membrane Glycoproteins
Mazindol
Behavior
Animal
Dose-Response Relationship
Drug
biology
Organic Chemistry
Membrane Transport Proteins
Rats
Stimulant
chemistry
biology.protein
Molecular Medicine
Indicators and Reagents
Pharmacophore
Reuptake inhibitor
Protein Binding
Synaptosomes
medicine.drug
Zdroj: Bioorganic & Medicinal Chemistry. 11:1123-1136
ISSN: 0968-0896
DOI: 10.1016/s0968-0896(02)00450-9
Popis: 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 Ki values of 7.3 and 8.9 μM 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 Ki 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 ED50 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.
Databáze: OpenAIRE
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