Synthesis, Biological Evaluation, and Docking Studies of Tetrahydrofuran- Cyclopentanone- and Cyclopentanol-Based Ligands Acting at Adrenergic α<sub>1</sub>- and Serotonine 5-HT<sub>1A</sub> Receptors

Prandi, Adolfo; Franchini, Silvia; Manasieva, Leda Ivanova; Fossa, Paola; Cichero, Elena; Marucci, Gabriella; Buccioni, Michela; Cilia, Antonio; Pirona, Lorenza; Brasili, Livio

doi:10.1021/jm200421e

Cited by 38 publications

(43 citation statements)

References 31 publications

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“…Accordingly, this method proved to be highly predictive in several case of homology models of proteins whose key residues were highlighted by mutagenesis experiments. [40][41][42] Thus, in this work the best scored site was selected for the following compound 1 docking simulation.…”

Section: Docking Studiesmentioning

confidence: 99%

In silico evaluation of human small heat shock protein HSP27: Homology modeling, mutation analyses and docking studies

Fossa¹,

Cichero²

2015

Bioorganic & Medicinal Chemistry

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Section: Docking Studiesmentioning

confidence: 99%

In silico evaluation of human small heat shock protein HSP27: Homology modeling, mutation analyses and docking studies

Fossa¹,

Cichero²

2015

Bioorganic & Medicinal Chemistry

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“…This residue is known to be also important for the binding of 5-HT 1A agonists. 16 In the exploration of 5-HT 1A receptor−ligand recognition, several studies have been carried out, 19,22,23 but no one, in our knowledge, further examined the CH−π interaction described in the current work. As the binding pocket of different GPCRs presents some homology, it will be interesting in the continuation of this work to evaluate this concept with other targets.…”

mentioning

confidence: 96%

“…Four main interactions known to be important for the receptor affinity 16 are found for all the compounds (Figure 1). …”

mentioning

confidence: 99%

Enhancing a CH−π Interaction to Increase the Affinity for 5-HT_1A Receptors

Liégeois

Lespagnard

Meneses‐Salas

et al. 2014

ACS Med. Chem. Lett.

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An electrostatic interaction related to a favorable position of the distal phenyl ring and a phenylalanine residue in the binding pocket would explain the higher 5-HT 1A affinity of a 4-phenyl-1,2,3,6-tetrahydropyridine (THP) analogue compared to the corresponding 4-phenylpiperazine analogue. To explore a possible reinforcement of this interaction to increase the affinity for 5-HT 1A receptors, different 4-substituted-phenyl analogues were synthesized and tested. The most important increase of affinity is obtained with two electron-donating methyl groups in positions 3 and 5. KEYWORDS: CH−π interaction, quinoxaline, carboxamide, arylpiperazine, electron-donating, docking R ecently, we reported that a 4-phenyl-1,2,3,6-tetrahydropyridine (THP) analogue was shown to be favorable compared to the corresponding 4-phenyl-piperazine one in terms of affinity for 5-HT 1A receptors in a series of 4-arylpiperazine-ethyl carboxamides. 1 An electrostatic interaction between the distal benzene ring of the molecule and a phenylalanine residue (Phe 6.52) particularly in the 5-HT 1A receptor binding pocket was suggested by molecular modeling approaches. 2 The almost coplanar orientation of both rings displayed in the 4-phenyl-THP compound appeared as an important spatial requirement for an optimal interaction with the 5-HT 1A receptor in the present series. This orientation should stabilize the ligand binding by an edge-to-face CH−π interaction between the phenyl ring of the 4-phenyl-THP compounds and the phenyl ring of the Phe 6.52 residue. 2 This would explain why the chemical modification of the piperazine ring into THP is favorable for receptor affinity.The electron donating/withdrawing properties of an aromatic substituent is an important factor for the electron density of the aromatic ring and consequently for the capacity of these rings to be involved in aromatic stacking interactions. 3 Some studies have already shown the impact of the electronic properties of the substituents on the stability of these interactions in ligand−receptor binding. 4,5 Therefore, by increasing the electronic density with an electron-donating group, we expected to reinforce the interaction between the distal benzene ring and the Phe 6.52 residue. The substituents were positioned either in position 4 or positions 3 and 5 of the distal ring in order to avoid a sterical constraint if present in position 2 or 6. To explore a possible opposite effect linked to the electronic properties of the substituents, electron-withdrawing atoms were also introduced. The THP derivatives were tested, in parallel with the corresponding arylpiperazine derivatives, for their affinity for 5-HT 1A receptors. The intrinsic activity of six selected compounds was also investigated using an electrophysiological approach.The target compounds were prepared by reaction of the appropriate primary amine with the appropriate acyl chloride (2-naphthoyl chloride or 2-quinoxaline chloride) as reported in Scheme 1. The crude amines were synthesized following a Gabriel pro...

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“…This tissue was used to assess α 1B -AR antagonism [39]. The spleen was removed and bisected longitudinally into two strips which were suspended in tissue baths containing Krebs solution of the following composition (mM): NaCl, 120; KCl, 4.7; CaCl 2 , 2.5; MgSO 4 , 1.5; KH 2 PO 4 , 1.2; NaHCO 3 , 20; glucose, 11; K 2 EDTA, 0.01.…”

Section: Rat Spleenmentioning

confidence: 99%

High affinity ligands and potent antagonists for the α1D-adrenergic receptor. Novel 3,8-disubstituted [1]benzothieno[3,2-d]pyrimidine derivatives

Romeo

Salerno

Pittalà

et al. 2014

European Journal of Medicinal Chemistry

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Synthesis, Biological Evaluation, and Docking Studies of Tetrahydrofuran- Cyclopentanone- and Cyclopentanol-Based Ligands Acting at Adrenergic α₁- and Serotonine 5-HT_1A Receptors

Cited by 38 publications

References 31 publications

In silico evaluation of human small heat shock protein HSP27: Homology modeling, mutation analyses and docking studies

In silico evaluation of human small heat shock protein HSP27: Homology modeling, mutation analyses and docking studies

Enhancing a CH−π Interaction to Increase the Affinity for 5-HT_1A Receptors

High affinity ligands and potent antagonists for the α1D-adrenergic receptor. Novel 3,8-disubstituted [1]benzothieno[3,2-d]pyrimidine derivatives

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Synthesis, Biological Evaluation, and Docking Studies of Tetrahydrofuran- Cyclopentanone- and Cyclopentanol-Based Ligands Acting at Adrenergic α1- and Serotonine 5-HT1A Receptors

Cited by 38 publications

References 31 publications

In silico evaluation of human small heat shock protein HSP27: Homology modeling, mutation analyses and docking studies

In silico evaluation of human small heat shock protein HSP27: Homology modeling, mutation analyses and docking studies

Enhancing a CH−π Interaction to Increase the Affinity for 5-HT1A Receptors

High affinity ligands and potent antagonists for the α1D-adrenergic receptor. Novel 3,8-disubstituted [1]benzothieno[3,2-d]pyrimidine derivatives

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Product

Resources

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Synthesis, Biological Evaluation, and Docking Studies of Tetrahydrofuran- Cyclopentanone- and Cyclopentanol-Based Ligands Acting at Adrenergic α₁- and Serotonine 5-HT_1A Receptors

Enhancing a CH−π Interaction to Increase the Affinity for 5-HT_1A Receptors