Synthesis and dopaminergic activity of 3-substituted 1-(aminomethyl)-3,4-dihydro-5,6-dihydroxy-1H-2-benzopyrans: characterization of an auxiliary binding region in the D1 receptor

The synthesis and dopaminergic activity of a series of C3 and nitrogen-substituted 1-(aminomethyl)-3,4-dihydro-5,6-dihydroxy-1H-2-benzopyrans (isochromans) is described. The synthesis of the compounds was stereospecific for the 1,3 cis isomer, and the enantioselective synthesis of both enantiomers o...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1991-08, Vol.34 (8), p.2561-2569
Main Authors: DeNinno, Michael P, Schoenleber, Robert, Perner, Richard J, Lijewski, Linda, Asin, Karen E, Britton, Donald R, MacKenzie, Robert, Kebabian, John W
Format: Article
Language:English
Subjects:
Adenylyl Cyclases - metabolism
agonists
Animals
benzopyran
Binding Sites
Binding, Competitive
Carps
Chemical Phenomena
Chemistry
Chromans - chemical synthesis
Chromans - metabolism
Chromans - pharmacology
Colforsin - pharmacology
Corpus Striatum - metabolism
Cyclic AMP - biosynthesis
derivatives
dopamine D2
evaluation
Exact sciences and technology
Heterocyclic compounds
Heterocyclic compounds with o, s, se, te hetero atom and condensed derivatives
Molecular Structure
Motor Activity - drug effects
Organic chemistry
Pituitary Neoplasms - metabolism
Preparations and properties
Rats
receptors
Receptors, Dopamine - metabolism
Receptors, Dopamine D1
Receptors, Dopamine D2
Rotation
Stereoisomerism
Structure-Activity Relationship
Tumor Cells, Cultured
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Summary:The synthesis and dopaminergic activity of a series of C3 and nitrogen-substituted 1-(aminomethyl)-3,4-dihydro-5,6-dihydroxy-1H-2-benzopyrans (isochromans) is described. The synthesis of the compounds was stereospecific for the 1,3 cis isomer, and the enantioselective synthesis of both enantiomers of one of the analogues (20) was achieved. It was determined that all of the dopaminergic activity resides in the [1R,3S] isomer. Generally, substitution at the C3 position provided compounds with very high potency (less than 10 nm EC50) and selectivity for the D1 receptor, with a wide range of intrinsic activities (60-160%). Analogues containing C3 substituents including aryl, arylalkyl, and cyclic and acyclic alkyl groups showed a marked enhancement of dopaminergic activity compared to the unsubstituted compound. As a class, the drugs were orally active in the rat rotation model with a very long duration of action.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00112a034