Aminoalkyl phenyl sulfones--a novel series of 5-HT7 receptor ligands

A novel series of 5-HT(7) receptor ligands has been identified and evaluated, providing compounds showing a broad spectrum of functional activities and good selectivity over selected receptors and ion channels.     

Identification of a novel series of 3-piperidinyl-5-sulfonylindazoles as potent 5-HT6 ligands

Cognitive dysfunction is a characteristic of various forms of dementia such as Alzheimer’s disease (AD) and a core feature of schizophrenia. As part of our continuing efforts to develop agents for cognitive enhancement, we have been focused on the 5-HT₆ receptor—one of the emerging therapeutic targets in this area. Herein, we report the identification of a novel series of 3-piperidinyl-5-sulfonylindazole derivatives as potent 5-HT₆ antagonists. The synthesis and SAR of this class of compounds are reported.     

Identification of a series of benzoxazoles as potent 5-HT6 ligands

As part of our continuing efforts to identify therapeutics for CNS diseases such as schizophrenia and Alzheimer’s disease (AD), we have been focused on the 5-HT₆ receptor in order to identify potent and selective ligands as a potential treatment for cognitive dysfunction. Herein we report the identification of a novel series of benzoxazole derivatives as potent 5-HT₆ ligands. The synthesis and detailed SAR of this class of compounds are reported. The compounds have been shown to be full antagonists in a cyclic AMP functional assay.     

A regiospecific synthesis of a series of 1-sulfonyl azepinoindoles as potent 5-HT6 ligands

A regiospecific synthesis of a series of 1-sulfonyl azepinoindoles as potent 5-HT6 ligands is reported.     

Design of novel multiple-acting ligands towards SERT and 5-HT2C receptors

This Letter describes our attempts to elaborate dually acting compounds possessing serotonin re-uptake transporter inhibitor and serotonin 5-HT_2C receptor antagonist properties. A novel series of 1,3-diphenylureas and N-phenylbenzamides have thus been prepared and evaluated. Based on its in vitro and in vivo activities, as well as pharmacokinetic profile, compound 16a was identified as a lead compound. The synthesis and structure–activity relationship of this series of compounds is presented herein.     

Solid-phase synthesis of 2,3-disubstituted indoles: discovery of a novel, high-affinity, selective h5-HT2A antagonist

The application of a novel solid-phase synthesis of 2,3-disubstituted indoles utilizing a carbamate indole linker is described resulting in the identification of the novel, high-affinity, selective h5-HT2A antagonist 19.     

4-Fluorosulfonylpiperidines: selective 5-HT2A ligands for the treatment of insomnia

Incorporation of fluorine at the 4-position of an existing series of sulfonyl piperidine 5-HT2A antagonists gave compounds with increased selectivity over the IKr potassium channel. This work led to the identification of 3b, a compound that gave no increase in QTc in the anesthetized dog up to plasma levels as high as 148 microM. Furthermore, 3b has been shown to increase slow-wave sleep bout duration and to decrease the number of awakenings in rats, indicating the potential utility of 5-HT2A antagonists in the treatment of insomnia.     

Identification of a novel series of selective 5-HT7 receptor antagonists

Novel 5-HT(7) receptor antagonists containing the benzocycloheptanone core were identified from high throughput screening. Molecular modelling and SAR studies have converted these intractable hits into a more potent, selective and tractable series, exemplified by compound (25), SB-691673.     

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.     

SAR of psilocybin analogs: discovery of a selective 5-HT 2C agonist

An SAR study of psilocybin and psilocin derivatives reveals that 1-methylpsilocin is a selective agonist at the h5-HT(2C) receptor. The corresponding phosphate derivative, 1-methylpsilocybin, shows efficacy in an animal model for obsessive-compulsive disorder, as does 4-fluoro-N,N-dimethyltryptamine. These results suggest a new area for development of novel 5-HT(2C) agonists with applications for drug discovery.     

Cyclic guanidines as dual 5-HT5A/5-HT7 receptor ligands: optimising brain penetration

The optimisation of molecular properties within a series of 2-amino dihydroquinazoline 5-HT5A/5-HT7 receptor ligands resulted in a significantly improved brain-to-plasma ratio, enhancing the pharmacological utility of these compounds. By modulating the lipophilicity and pKa, a 20-fold increase in brain-to-plasma ratio could be achieved, leading to micromolar brain concentrations after oral administration. The enantiomers of one representative of this series of improved compounds were separated, and the configuration of the eutomer was determined by X-ray crystallography.     

Cyclic guanidines as dual 5-HT5A/5-HT7 receptor ligands: structure-activity relationship elucidation

The optimisation of affinity and selectivity in a novel series of dual 5-HT5A/5-HT7 receptor ligands is described. Brain penetrant 2-aminodihydroquinazolines with low nanomolar affinities were identified.     

Identification of the binding sites and selectivity of sarpogrelate,a novel 5-HT2 antagonist,to human 5-HT2A, 5-HT2B and 5-HT2C receptor subtypes by molecular modeling

The aim of the present study was to investigate the binding sites interactions and the selectivity of sarpogrelate to human 5-HT(2) receptor family (5-HT(2A), 5-HT(2B) and 5-HT(2C) receptor subtypes) using molecular modeling. Rhodopsin (RH) crystal structures were used as template to build structural models of the human serotonin-2A and -2C receptors (5-HT(2A)R, 5-HT(2C)R), whereas for 5-HT(2B)R, we used our previously published three-dimensional (3D) models based on bacteriorhodopsin (BR). Sarpogrelate, a novel 5-HT(2)R antagonist, was docked to the receptors. Molecular dynamics (MD) simulations produced the strongest interaction for 5-HT(2A)R/sarpogrelate complex. Upon binding, sarpogrelate constraints aromatic residues network (Trp(3.28), Phe(5.47), Trp(6.48), Phe(6.51), Phe(6.52) in 5-HT(2A)R; Phe(3.35), Phe(6.51), Trp(7.40) in 5-HT(2B)R; Trp(3.28), Phe(3.35), Phe(5.47), Trp(6.48), Phe(6.51), Phe(6.52) in 5-HT(2C)R) in a stacked configuration, preventing activation of the receptor. The models suggest that the structural origin of the selectivity of sarpogrelate to 5-HT(2A)R vs both 5-HT(2B)R and 5-HT(2C)R comes from the following results: (1) The tight interaction between the antagonist and the transmembrane domain (TMD) 3. Asp(3.32) neutralizes the cationic head and interacts simultaneously with carboxylic group hydrogen of the antagonist molecule. (2) Due to steric hindrance, Ser(5.46) (vs Ala(5.46) in 5HT(2B) and 5HT(2C)) prevents sarpogrelate to enter deeply inside the hydrophobic core of the helix bundle and to interact with Pro(5.50). (3) The side chain of Ile(4.56) (vs Ile(4.56) in 5HT(2B)R and Val(4.56) in 5HT(2C)R) constraints sarpogrelate to adjust its position by translating toward the strongly attractive Asp(3.32). These results are in good agreement with binding affinities (pKi) of sarpogrelate for 5-HT(2) receptor family expressed in transfected cell.     

Benzimidazolone-based serotonin 5-HT1A or 5-HT7R ligands: Synthesis and biological evaluation

A new group of serotoninergic 5-HT_1A or 5-HT₇ receptor ligands was identified. These compounds were designed and synthesized on a benzimidazolone scaffold and they enrich the well-known arylpiperazine class of 5-HT ligands. Diverse pharmacomodulations induced a shift in the affinity and selectivity profile with final identification of new potent hits.     

Substituted furo[3,2-b]pyridines: novel bioisosteres of 5-HT 1F receptor agonists

Synthesis and evaluation of a series of 2,3,5- and 3,5-substituted furo[3,2-b]pyridines were undertaken in order to investigate their utility as bioisosteres of 5-HT(1F) receptor agonist indole analogues, 1-3. The replacement proved to be effective, providing compounds with similar 5-HT(1F) receptor affinity and improved selectivity when compared with the indole analogues. Through these studies we identified 4-fluoro-N-[3-(1-methyl-piperidin-4-yl)-furo[3,2-b]pyridin-5-yl]-benzamide (5), a potent and selective 5-HT(1F) receptor agonist with the potential to treat acute migraine.     

Synthesis and binding properties of novel selective 5-HT3 receptor ligands

This work reports on the synthesis and affinities for the 5-HT(3) versus the 5-HT(4) receptor of new piperazinyl-substituted thienopyrimidine derivatives 20-45 with a view to identify potent and selective ligands for the 5-HT(3) receptor. Some of the new compounds show good affinity for the 5-HT(3) receptor and, notably, do not display any affinity for the 5-HT(4) receptor. 4-(4-Methyl-1-piperazinyl)-2-methylthio-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidine 31 exhibits the highest affinity for the 5-HT(3) receptor (Ki = 33 nM) and behaves as noncompetitive antagonist.     

1,2,3,4-tetrahydroisoquinoline derivatives: a new class of 5-HT1A receptor ligands

Three series of new N-substituted 1,2,3,4-tetrahydroisoquinolines with 2-, 3-, and 4-membered alkyl chains (a, b, and c, respectively) were synthesized, and the effect of some structural modifications on their 5-HT1A receptor affinities and functional properties was discussed. It was found that the volume of the terminal amide substituent was a crucial parameter which determined 5-HT1A receptor affinities of the tested compounds, while the in vivo activity seemed to depend on both the R-volume and the length of a hydrocarbon chain. It was demonstrated that the most active ligands behaved like agonists or partial agonists at postsynaptic 5-HT1A receptors.     

Design and synthesis of dual 5-HT1A and 5-HT7 receptor ligands

5-HT_1A and 5-HT₇ receptors have been at the center of discussions recently due in part to their major role in the etiology of major central nervous system diseases such as depression, sleep disorders, and schizophrenia. As part of our search to identify dual targeting ligands for these receptors, we have carried out a systematic modification of a selective 5HT₇ receptor ligand culminating in the identification of several dual 5-HT_1A and 5-HT₇ receptor ligands. Compound 16, a butyrophenone derivative of tetrahydroisoquinoline (THIQ), was identified as the most potent agent with low nanomolar binding affinities to both receptors. Interestingly, compound 16 also displayed moderate affinity to other clinically relevant dopamine receptors. Thus, it is anticipated that compound 16 may serve as a lead for further exploitation in our quest to identify new ligands with the potential to treat diseases of CNS origin.     

Studies on a series of potent, orally bioavailable, 5-HT(1) receptor ligands

A series of 5-(piperidinylethyloxy)quinoline 5-HT(1) receptor ligands have been studied by elaboration of the series of dual 5-HT(1)-SSRIs reported previously. These new compounds display a different pharmacological profile with potent affinity across the 5-HT(1A), 5-HT(1B) and 5-HT(1D) receptors and selectivity against the serotonin transporter. Furthermore, they have improved pharmacokinetic profiles and CNS penetration.     

Identification and optimisation of 5-amino-7-aryldihydro-1,4-diazepines as 5-HT2A ligands

A several series of low molecular weight 5-HT(2A) leads were identified from an analysis of HTS data, the exploration of SAR and optimization of one series using parallel synthesis are described, affording compound 22 (5-HT(2A) IC(50) 1.1 nM).