Drug design via pharmacophore identification. Dopaminergic activity of 3H-benz[e]indol-8-amines and their mode of interaction with the dopamine receptor

The design and synthesis of a series of 3H-benz[e]indol-8-amines are described. Two of the compounds are potent, orally active dopaminergic agents as established by their ability to induce contralateral turning in rats with unilateral 6-hydroxydopamine-induced lesions of the nigrostriatal pathway, t...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1986-05, Vol.29 (5), p.648-654
Main Authors: Asselin, Andre A, Humber, Leslie G, Voith, Katherine, Metcalf, Geoffrey
Format: Article
Language:English
Subjects:
Amines - pharmacology
Animals
Catalepsy - chemically induced
Chemistry
Corpus Striatum - drug effects
Exact sciences and technology
Heterocyclic compounds
Heterocyclic compounds with only one n hetero atom and condensed derivatives
Hydroxydopamines - pharmacology
Indoles - pharmacology
Male
Mice
Motor Activity - drug effects
Optical Rotation
Organic chemistry
Oxidopamine
Preparations and properties
Rats
Rats, Inbred Strains
Receptors, Dopamine - metabolism
Reserpine - pharmacology
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Summary:The design and synthesis of a series of 3H-benz[e]indol-8-amines are described. Two of the compounds are potent, orally active dopaminergic agents as established by their ability to induce contralateral turning in rats with unilateral 6-hydroxydopamine-induced lesions of the nigrostriatal pathway, to induce ambulation in rats rendered akinetic by bilateral injections of 6-hydroxydopamine into the anterolateral hypothalamus, and to antagonize reserpine-induced catalepsy in mice. The dopamine agonist activity of the 3H-benz[e]indol-8-amines establishes that a pyrrolo ring and a phenolic hydroxyl group can interact similarly with the dopamine receptor and provides evidence for the existence of a hydrogen-bond acceptor nucleus on the dopamine receptor macromolecule that is involved in the behavioral manifestations of dopamine agonists.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00155a011