Potent, selective tetrahydro-beta-carboline antagonists of the serotonin 2B (5HT2B) contractile receptor in the rat stomach fundus.

A series of potent, selective 5HT2B receptor antagonists has been identified based upon yohimbine, with SAR studies resulting in a 1000-fold increase in 5HT2B receptor affinity relative to the starting structure (-log KBS > 10.0 have been obtained). These high-affinity tetrahydro-beta-carboline antagonists are able to discriminate among the 5HT2 family of serotonin receptors, with members of the series showing selectivities of more than 100-fold versus both the 5HT2A and 5HT2C receptors based upon radioligand binding and functional assays.

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

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.

Interaction of 5-hydroxykynurenamine, L-kynurenine and kynuramine with multiple serotonin receptors in smooth muscle.

The enzymatic formation of kynurenine derivatives from tryptophan and the regulation of this metabolic pathway by both tryptophan concentrations and plasma cortisol concentrations have raised the possibility that the kynurenine derivatives, L-kynurenine, kynuramine and 5-hydroxykynurenamine (5-OH-kynurenamine) may be important as endogenous agonists or antagonists at serotonin (5-HT) receptors in smooth muscle. In fact, 5-OH-kynurenamine was an agonist at 5-HT2 receptors in the rat jugular vein and aorta, at 5-HT3 (neuronal "M") receptors in the guinea pig ileum and at 5-HT receptors in the rat stomach fundus. Maximal contractile responses to 5-OH-kynurenamine in these three smooth muscle preparations were similar to those produced by 5-HT, although 5-OH-kynurenamine was approximately 10- to 100-fold less potent than 5-HT as a contractile agonist.

2,3-Dialkyl(dimethylamino)indoles: interaction with 5HT1, 5HT2, and rat stomach fundal serotonin receptors.

2,3-Dialkyl(dimethylamino)indoles, synthesized via the Fisher indole synthesis, were found to weakly bind to 5HT1 and 5HT2 sites in brain cortical membranes (IC50 greater than 1 microM at both sites for all compounds). These (dimethylamino)indoles were relatively potent antagonists of the serotonin receptor in the rat stomach fundus. At higher concentrations, several of the compounds were weak agonists at this receptor.