1-(Arylsulfonyl)-2,3-dihydro-1H-quinolin-4-one derivatives as 5-HT(6) serotonin receptor ligands

Piperazinyl derivatives of 1-(arylsulfonyl)-2,3-dihydro-1H-quinolin-4-ones have been identified with high binding affinities for 5-HT₆ receptor. In particular, 2-methyl-5-(N-methyl-piperazin-1-yl)-1-(naphthalene-2-sulfonyl)-2,3-dihydro-1H-quinolin-4-one (8g) exhibits high binding affinity toward 5-HT₆ (IC₅₀ = 8 nM) receptor with good selectivity over other serotonin and dopamine receptors.     

1,2,3,4-tetrahydrocarbazoles as 5-HT6 serotonin receptor ligands

An investigation of the structure-affinity relationships for the binding of 4-(N,N-dimethylaminomethyl)-N(9)-arylsulfonyl-9H-1,2,3,4-tetrahydrocarbazoles (conformationally-constrained analogues of the benzenesulfonyltryptamine 5-HT(6) antagonist MS-245) at human 5-HT(6) receptors revealed that various arylsulfonyl substituents are tolerated and that the 4-(N,N-dimethylaminomethyl) group is not required for binding. In particular, N(9)-(4-aminobenzenesulfonyl)-9H-1,2,3,4-tetrahydrocarbazole (20, K(i)=29 nM) was found to bind with high affinity and represents the first member of a new structural class of agents with 5-HT(6) antagonist properties (pA(2)=7.0; cAMP hydrolysis assay).     

1-(2-Aminoethyl)-3-(arylsulfonyl)-1H-indoles as novel 5-HT6 receptor ligands

Novel 1-(2-aminoethyl)-3-(arylsulfonyl)-1H-indoles were prepared. Binding assays indicated they are 5-HT(6) receptor ligands, among which N,N-dimethyl-N-(2-[3-(1-naphthylsulfonyl)-1H-indol-1-yl]ethyl)amine 8t and N-methyl-N-(2-[3-(1-naphthylsulfonyl)-1H-indol-1-yl]ethyl)amine 8u showed high affinity for 5-HT(6) receptors with K(i)=3.7 and 5.7 nM, respectively.     

4-(2-Aminoethoxy)-N-(phenylsulfonyl)indoles as novel 5-HT6 receptor ligands

The preparation of a novel class of 4-(2-aminoethoxy)-N-(phenylsulfonyl)indoles which exhibit high affinity towards the 5-HT6 receptor is reported here. Among these compounds, 4-(2-methylaminoethoxy)-N-(phenylsulfonyl)indole 5g showed superior affinity (Ki = 1 nM) towards the 5-HT6 receptor as well as excellent selectivity (> 2000-fold) against the closely related subtype 5-HT7 receptor.     

N-arylsulfonyl-2-vinyltryptamines as new 5-HT6 serotonin receptor ligands

Several new 2-vinyl-Nb,Nb-dimethyltryptamines were prepared using Fischer indole synthesis followed by simple functional group transformations and evaluated on 5-HT4, 5-HT5, 5-HT6 and 5-HT7 serotonin receptors. It was found that 2-vinyl substitution conferred a potent and selective 5-HT6 binding activity to these molecules which could be enhanced by Na-arylsulfonyl substituents.     

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.     

2-(Anilino)imidazolines and 2-(benzyl)imidazoline derivatives as h5-HT1D serotonin receptor ligands

2-(Anilino)imidazolines were identified as novel human 5-HT(1D) receptor ligands, but offered no particular advantage over previously reported 2-(benzyl)imidazolines. Pharmacokinetic and functional data were obtained for selected 2-(benzyl)imidazoline derivatives.     

Synthesis and structure-activity relationship of novel conformationally restricted analogues of serotonin as 5-HT6 receptor ligands

5-Hydroxytryptamine 6 receptors (5-HT(6)R) are being perceived as the possible target for treatment of cognitive disorders as well as obesity. The present article deals with the design, synthesis, in vitro binding and structure-activity relationship of a novel series of tetracyclic tryptamines with the rigidized N-arylsulphonyl, N-arylcarbonyl and N-benzyl substituents as 5-HT(6) receptor ligands. The chiral sulphonyl derivatives 15a and 17a showed high affinity at 5-HT(6)R with the K(i) of 23.4 and 20.5?nM, respectively. The lead compound from the series 15a has acceptable ADME properties, adequate brain penetration and is active in animal models of cognition like Novel Object Recognition Task (NORT) and water maze.     

1-(2-Aminoethyl)-3-(arylsulfonyl)-1H-pyrrolopyridines are 5-HT6 receptor ligands

1-(2-Aminoethyl)-3-(arylsulfonyl)-1H-pyrrolopyridines were prepared. Binding assays indicated they are 5-HT₆ receptor ligands, among which 6f and 6g showed high affinity for 5-HT₆ receptors with K_i = 3.9 and 1.7 nM, respectively.     

N1-(Benzenesulfonyl)tryptamines as novel 5-HT6 antagonists

N-Benzenesulfonyl-5-methoxy-N,N-dimethyltryptamine (BS/5-OMe DMT; 5) was shown to bind at human 5-HT6 serotonin receptors with high affinity (Ki = 2.3 nM) relative to serotonin (Ki = 78 nM). Structural variation failed to result in significantly enhanced affinity. BS/5-OMe DMT acts as an antagonist of 5-HT-stimulated adenylate cyclase (pA2 = 8.88 nM) and may represent the first member of a novel class of 5-HT6 antagonists.     

2-Alkyl-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indoles as novel 5-HT6 receptor agonists

A series of 2-alkyl-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indoles were synthesized and evaluated for their 5-HT6 activity. The most potent agonist in this series was 5-chloro-2-methyl-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole with an IC50=7.4 nM in 3H-LSD binding and an EC50=1.0 nM in a functional assay measuring production of cyclic AMP.     

Arene- and quinoline-sulfonamides as novel 5-HT7 receptor ligands

Novel arene- and quinolinesulfonamides were synthesized using different solutions and a solid-support methodology, and were evaluated for their affinity for 5-HT(1A), 5-HT(2A), 5-HT(6), and 5-HT(7) receptors. Compound 54 (N-Ethyl-N-[4-(1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinolin-2-yl)butyl]-8-quinolinesulfonamide) was identified as potent 5-HT(7) antagonist (K(i)=13 nM, K(B)=140 nM) with good selectivity over 5-HT(1A), 5-HT(2A), 5-HT(6) receptors. In the FST in mice, it reduced immobility in a manner similar to the selective 5-HT(7) antagonist SB-269970.     

Synthesis of potent and selective serotonin 5-HT1B receptor ligands

A series of serotonin 5-HT1B ligands were synthesized and evaluated for their potency and selectivity against other 5-HT receptor subtypes. Many of these new compounds displayed high affinity and selectivity for the 5-HT1B receptor and compound 6c was found to have the in vitro binding profile necessary for development as a PET radioligand.     

1-(Bicyclopiperazinyl)ethylindoles and 1-(homopiperazinyl)ethyl-indoles as highly selective and potent 5-HT(7) receptor ligands

A novel series of 1-(bicyclopiperazinyl)ethylindole and 1-(homopiperazinyl)ethyl-indole derivatives was synthesized and found to be potent and selective 5-HT(7) receptor ligands.     

N-Propylnoraporphin-11-O-yl carboxylic esters as potent dopamine D(2) and serotonin 5-HT(1A) receptor dual ligands

A small series of N-propylnoraporphin-11-O-yl carboxylic esters with variant ester lengths were synthesized and their binding potencies at dopamine receptors (D(1), D(2)) and serotonin receptors (5-HT(1A), 5-HT(2A)) were evaluated. Monoesters 3a-f showed binding potency of 100 nM or less for the D(2) receptor, and potency of 10-30 nM for the 5-HT(1A) receptor. Butyryl ester 3d was found to be the best compound possessing the highest potency for both receptors, with K(i) values of 55 and 12 nM for D(2) and 5-HT(1A) receptors, respectively. There is no correlation between the binding potency and the length of the monoesters, but the diesters 9 and 10 were inactive for the D(2) receptor. The dual binding profile of these monoesters for the D(2) and 5-HT(1A) receptors may be useful for the treatment of neuropsychiatric disorders.     

Synthesis of new 1,2,3-benzotriazin-4-one-arylpiperazine derivatives as 5-HT1A serotonin receptor ligands

A series of novel 1,2,3-benzotriazin-4-one derivatives was prepared and evaluated as ligands for 5-HT receptors. Radioligand binding assays proved that the majority of the novel compounds behaved as good to excellent ligands at the 5-HT1A receptor, some of which were selective with respect 5-HT2A and 5-HT2C receptors. Six analogues (1a, 2a, 2b, 2c, 2e and 2i) were selected and further evaluated for their binding affinities on D1, D2 dopaminergic and alpha1-, alpha2-adrenergic receptors. A o-OCH3 derivative (2e) bound at 5-HT1A sites with subnanomolar affinity (IC50 = 0.059 nM) and shows high selectivity over all considered receptors and may offer a new lead for the development of therapeutically efficacious agents.     

Design and synthesis of novel series of 5-HT6 receptor ligands having indole,a central aromatic core and 1-amino-4 methyl piperazine as a positive ionizable group

The exclusive distribution of 5-HT₆ receptor in the brain regions and high affinity for antipsychotic and antidepressant drugs makes 5-HT₆ receptor a promising target in treatment of CNS diseases. Based on a pharmacophore model reported in the literature, we designed and synthesized a novel series of 5-HT₆ receptor ligands having indole as a central aromatic core and 1-amino-4-methyl piperazine as positive ionizable group. Out of 32 compounds we have successfully identified 10 new compounds as 5-HT₆ receptor antagonists. The structure–activity relationship (SAR) studies have been carried out by mapping the compounds with the 3D QSAR model.     

3-(Arylsulfonyl)-1-(azacyclyl)-1H-indoles are 5-HT6 receptor modulators

Novel 3-(arylsulfonyl)-1-(azacyclyl)-1H-indoles 6 were synthesized as potential 5-HT₆ receptor ligands, based on constraining a basic side chain as either a piperidine or a pyrrolidine. Many of these compounds had good 5-HT₆ binding affinity with K_i values <10 nM. Depending on substitution, both agonists (e.g., 6o: EC₅₀ = 60 nM, E_max = 70%) and antagonists (6y: IC₅₀ = 17 nM, I_max = 86%) were identified in a 5-HT₆ adenylyl cyclase assay.     

Novel 7-phenylsulfanyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indoles as dual serotonin 5-HT2C and 5-HT6 receptor ligands

Novel 7-phenylsulfanyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indoles are synthesized using a six-step protocol. Notably, the synthesis route make use of a new and improved ring-closing methodology for the assembly of the hexahydro-pyrazino[1,2-a]indole scaffold, which is based on intramolecular C–H insertion of a carbene. The compounds act as dual serotonin 5-HT_2C- and 5-HT₆-ligands.     

Design, synthesis and preliminary screening of novel 3-(2-N,N-dimethylaminoethylthio) indole derivatives as potential 5-HT(6) receptor ligands

The synthesis and potential 5-hydroxytryptamine(6) receptor (5-HT6R) antagonist activity of a novel series of N-arylsulfonyl-3-(2-N,N-dimethylaminoethylthio) indoles has been reported. The molecular modeling, synthesis and in-vitro radioligand binding data of this series are discussed. The present article describes 37 derivatives of the title series. It was observed that the increased side-chain length with the insertion of a sulfur atom did not lead to the loss of binding affinity of these compounds, although the affinities were reduced. The compounds exhibited moderate affinity and selectivity to human 5-HT6 receptors.