6-Methylergoline-8-carboxylic acid esters as serotonin antagonists: N1-substituent effects on 5HT2 receptor affinity

Article abstract of DOI:10.1021/jm00393a024

Three series of 6-methylergoline-8-carboxylic acid esters with various alkyl substituents in the N¹-position were prepared and their 5HT₂ receptor affinities measured. Some overlap occurred in the 5HT₂ receptor affinities of the different ester series, indicating that both the ester side chain and the indole substituent influenced 5HT₂ receptor affinity. While 5HT₂ receptor affinity was affected by the structure of the ester side chain, the N¹-substituent played a more crucial role in determining 5HT₂ receptor affinity. When the ester side chain was held constant, maximal 5HT₂ receptor affinity for that series of esteres was obtained when the N¹-substituent was isopropyl. Smaller substituents in the N¹-position resulted in reduced 5HT₂ receptor affinity. Groups C₄ or larger in the N¹-position resulted in a further decline in 5HT₂ receptor affinity. The importance of the N¹-substituent in determining 5HT₂ receptor affinity was further substantiated when several 2-methyl-3-ethyl-5-(dimethylamino)indoles with various N¹-substituents were tested. Again, maximal 5HT₂ receptor affinity was obtained when the N¹-substituent was isopropyl.