Synthesis of substituted indole derivatives as potential dopamine agonists
Abstract
The ergot alkaloids are a class of compounds with a broad range of pharmacological activity. One aspect of the pharmacology is their potent dopamine (D-2) activity. Earlier research has led to the synthesis of 4-(2-$N$,$N$-di-$n$-propylaminoethyl)indole (DPAI), which was shown to have moderate prolactin-inhibitory activity (D-2 activity) and selective dopamine autoreceptor activity. This research initially involved the modification of the lead compound DPAI with a goal of improving the potency and selectivity of the dopamine activity. Various $N$,$N$-dialkylaminoethyl indoles were synthesized, and the compound with the $N$-3-(methylthio)propyl-$N$-($n$-propyl)aminoethyl side chain was the most potent compound in the inhibition of serum prolactin levels in rats (decrease of 78% at a dose of 2 mg/kg). It appears that one of the alkyl group must be $n$-propyl for maximum dopamine activity, and both groups must not be larger than $n$-propyl. The compound 4-(2-aminoethyl)indole was reacted via an intramolecular Mannich reaction to form a novel heterocyclic ring system 3,4,5,6-tetrahydro-1$H$-azepino(3,4,5-cd) indole (THAI). Various 3 and 4-substituted THAI derivatives were synthesized, but none showed any significant activity in the prolactin-inhibition prescreen. These compounds are also under investigation as D-1 and serotonin agonists. A series of 3$\sp\prime$-(2-$N$,$N$-di-$n$-propylaminoethyl)aniline derivatives was synthesized to examine the ability of the NH group to mimic the meta-OH group by adjusting the NH acidity. The methanesulfonanilide derivative showed potent prolactin-inhibitory activity (decrease of 76% of prolactin levels). This activity may be due to the similar acidity of the methanesulfonanilide group and the catechol moiety of dopamine. The 5 and 6-substituted DPAI isomers were synthesized, and a 7-azaindole analog of tryptamine was also prepared.
Degree
Ph.D.
Advisors
Cassady, Purdue University.
Subject Area
Pharmacology
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