The design and synthesis of substituted indole derivatives as potential dopamine agonists
Abstract
The ergot alkaloids as a class have shown a broad range of pharmacological activity. One aspect of their pharmacology is potent activity at dopamine D-2 receptors. Extensive research in our laboratory has been directed towards finding more selective agents by elucidation of the ergoline pharmacophore responsible for dopamine receptor stimulation. One phase of this project investigated the effect of incorporating the ethylamine side chain of (2-N,N-di-n-propylaminoethyl)indole (DPAI) into conformationally restricted systems. These compounds did not possess dopaminergic activity, but did exhibit serotinergic activity. Additionally, a new approach to azepino (3,4,5-cd) indoles was developed that enabled ring substituted derivatives to be synthesized. A number of analogs of DPAI were made in an effort to improve autoreceptor selectivity and to investigate a recent hypothesis in the literature that N-n-propyl substituents may be detrimental to autoreceptor selectivity. These included seco-ergoline derivatives and a number of compounds with functional groups on the alkyl chains. Finally, the 3-methyl analog of DPAI was synthesized to study whether the isotryptamines may bind in an anti-ergoline conformation. These compounds are currently undergoing pharmacological evaluation.
Degree
Ph.D.
Advisors
Cassady, Purdue University.
Subject Area
Organic chemistry
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