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Monoamine transporter binding, locomotor activity, and drug discrimination properties of 3-(4-substituted-phenyl)tropane-2-carboxylic acid methyl ester isomers.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2004 Dec 02; Vol. 47 (25), pp. 6401-9. - Publication Year :
- 2004
-
Abstract
- The monoamine transporter binding properties, gross behavior, and locomotor activity effects in mice and drug discrimination results in cocaine-trained rats of the 2 beta,3beta-, 2 beta,3 alpha-, 2 alpha,3beta-, and 2 alpha,3 alpha-isomers of several 3-(4-substituted-phenyl)tropane carboxylic acid methyl esters were compared (2a-f, 3a-f, 4a-f, and 5b,c). The 2 beta,3beta-isomer showed the highest affinity for the dopamine transporter (DAT), and the 2 beta,3 alpha-isomer showed the next highest affinity. The order of potency for the 2 beta,3beta-isomer is 4'-chloro (2c) = 4'-iodo (2e) > 4'-bromo (2d) = 4'-methyl (2f) > 4'-fluoro (2b) > 4'-hydrogen (2a). In the case of the 2 beta,3 alpha-isomer, the order of affinity was 4'-bromo (3d) > 4'-iodo (3e) = 4'- chloro (3c) > 4'-methyl (3f) > 4'-fluoro (3b) > 4'-hydrogen (3a). The 4'-hydrogen, 4'-fluoro, and 4'-methyl 2 alpha,3beta-isomers, 4a, 4b, and 4f, had the lowest affinity for the DAT. While most of the compounds showed their highest affinity at the DAT, none were selective relative to the other two monoamine transporters. In general, the 2 alpha,3 alpha- and 2 alpha,3beta-isomers were more toxic (death and convulsions) than the 2 beta,3beta- and 2 beta,3 alpha-isomers. With the exception of the 2 alpha,3 alpha-isomers, all compounds produced the locomotor activity stimulation typical of dopaminergic drugs. The ED(50) ranges for the 2 beta,3beta- (2a-f), 2 beta,3 alpha- (3a-f), and 2 alpha,3beta-isomers (4a-f) in the locomotor assay were 0.1-1.2, 6.6-21.8, and 2.4-11.7 mg/kg, respectively. With the exception of the 2 alpha,3 alpha-isomer, all compounds generalized to cocaine. The 2 beta,3beta-isomers were at least 10-fold more potent than cocaine and the other three sets of isomers in this test.
- Subjects :
- Animals
Binding, Competitive
Central Nervous System Stimulants pharmacology
Cocaine pharmacology
Discrimination Learning drug effects
Dopamine Plasma Membrane Transport Proteins
Esters
Isomerism
Male
Mice
Norepinephrine Plasma Membrane Transport Proteins
Radioligand Assay
Rats
Rats, Sprague-Dawley
Serotonin Plasma Membrane Transport Proteins
Structure-Activity Relationship
Tropanes chemistry
Tropanes pharmacology
Discrimination, Psychological drug effects
Membrane Glycoproteins metabolism
Membrane Transport Proteins metabolism
Motor Activity drug effects
Nerve Tissue Proteins metabolism
Symporters metabolism
Tropanes chemical synthesis
Subjects
Details
- Language :
- English
- ISSN :
- 0022-2623
- Volume :
- 47
- Issue :
- 25
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 15566309
- Full Text :
- https://doi.org/10.1021/jm0401311