New 1,2,3,9-tetrahydro-4H-carbazol-4-one derivatives: analogues of HEAT as ligands for the alpha1-adrenergic receptor subtypes.

With the aim to develop new ligands able to discriminate among the three subtypes of alpha1-adrenergic receptors (alpha1A-AR, alpha1B-AR, and alpha1D-AR), a series of new 1,2,3,9-tetrahydro-4H-carbazol-4-ones bearing a 3-[[[2-(4-hydroxyphenyl)ethyl]amino]methyl] or a 3-[[4-(2-substitutedphenyl)piperazin-1-yl]methyl] side chain were synthesized. The general structure of the new compounds is reminiscent of HEAT and RN5, two potent alpha1-AR antagonists which show high affinities for all three alpha1-AR subtypes. Some derivatives in which one ring of the tetrahydrocarbazolone system was opened were also prepared. Compounds were tested in radioligand binding assays on human cloned alpha1A-AR, alpha1B-AR, and alpha1D-AR subtypes stably expressed in HEK293 cells. They showed moderate to good affinities, although their selectivity among the receptor subtypes hardly reached one order of magnitude.

A facile synthesis of new 2-carboxamido-3-carboxythiophene and 4,5,6,7-tetrahydro-2-carboxamido-3-carboxythieno[2,3-c]pyridine derivatives as potential endothelin receptors ligands.

Endothelins (ETs) are the most ubiquitous, highly potent and unusually long-lasting peptidic constrictors of human vessels known. Elevated levels of the plasma concentration of ETs were observed in several diseases such as hypertension, acute myocardial infarction, congestive heart failure, renal failure, pulmonary hypertension, and atherosclerosis. ETs exert their activities via specific seven-transmembrane, G protein-coupled receptors. To date two receptor subtypes, endothelin A (ET(A)) and endothelin B (ET(B)), have been identified and cloned. A literature survey revealed that a number of compounds that bind ET receptors with affinity and selectivity are known, nevertheless these compounds belong only to few chemical classes. The aim of this work is the identification of an "hit compound" with novel chemical structure endowed with reasonable ET affinity and selectivity. Accordingly, new variously substituted 2-carboxamido-3-carboxythiophene derivatives (29-52) were synthesized. These compounds were tested for their ability to inhibit ETs binding in radioligand binding assay using CHO cells stably expressing human ET(A) and ET(B) receptors.

[1,2,4]Triazole derivatives as 5-HT(1A) serotonin receptor ligands.

A series of new 4-amino-3-[3-[4-(2-methoxy or nitro phenyl)-1-piperazinyl] propyl]thio]-5-(substitutedphenyl)[1,2,4]triazoles 11a-t was synthesized in order to obtain compounds with high affinity and selectivity for 5-HT(1A) receptor over the alpha(1)-adrenoceptor. A series of isomeric 4-amino-2-[3-[4-(2-methoxy or nitro phenyl)-1-piperazinyl]propyl]-5-(substitutedphenyl)-2,4-dihydro-3H[1,2,4]triazole-3-thiones 12a-r was also isolated and characterized. New compounds were tested to evaluate their affinity for 5-HT(1A) receptor and alpha(1)-adrenoceptor in radioligand binding experiments. As a general trend, triazoles 11a-t showed a preferential affinity for the 5-HT(1A) receptor whereas isomeric 2,4-dihydro-3H[1,2,4]triazole-3-thiones 12a-r preferentially bind to the alpha(1)-adrenoceptor site. Several molecules showed affinities in the nanomolar range and 4-amino-3-[3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl]thio]-5-(4-propyloxy-phenyl)[1,2,4]triazole (11o) was the most selective derivative for the 5-HT(1A) receptor (K(i) alpha(1)/K(i) 5-HT(1A)=55). The decrease in 5-HT(1A) receptor selectivity in 3-[3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl]thio]-5-(substitutedphenyl)[1,2,4] triazole 14a-b, lacking in the amino group in 4-position of the triazole ring, in comparison with their analogues in the series 11a-t, suggest that the amino function represents a critical structural feature in determining 5-HT(1A) receptor selectivity in this class of compounds.