Synthesis and Structure−Activity Relationships of a New Model of Arylpiperazines. 1. 2-[[4-(o-Methoxyphenyl)piperazin-1-yl]methyl]-1,3- dioxoperhydroimidazo[1,5-a]pyridine:  A Selective 5-HT1A Receptor Agonist

López-Rodrı́guez, Marı́a L.; Rosado, M. L.; Benhamú, Bellinda; Morcillo, M. J.; Sanz, Antonio; Orensanz, Luis M.; Beneitez, M. E.; Fuentes, JoséA.; Manzanares, Jorge

doi:10.1021/jm960416g

Cited by 61 publications

(24 citation statements)

References 28 publications

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“…The unsubstituted indolepropylphenylpiperazine (12a) showed a marked affinity for 5-HT 1A , which increased after the introduction of a methoxyl group in the ortho position (12b). This result agrees with a number of previous studies 11,14,[24][25][26] in which the 2-methoxyarylpiperazine derivative exhibited one of the highest affinities of the series.…”

Section: Resultssupporting

confidence: 93%

Synthesis, 5-Hydroxytryptamine1A Receptor Affinity and Docking Studies of 3-[3-(4-Aryl-1-piperazinyl)-propyl]-1H-Indole Derivatives

Pessoa‐Mahana

Núñez

Araya‐Maturana

et al. 2012

CHEMICAL & PHARMACEUTICAL BULLETIN

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A series of 3-[3-(4-aryl-1-piperazinyl)-propyl]-1H-indole derivatives (12a-hKey words indolylalkylarylpiperazine; 5-hydroxytryptamine 1A receptor; docking; binding; synthesis Serotonin (5-hydroxytryptamine, 5-HT) is an important neurotransmitter that mediates various physiological and pathological processes in the peripheral and central nervous system (CNS) by interacting with several different receptors.1-3) The 5-HT 1A receptor sub-population has attracted considerable attention in the drug discovery field.4-7) It is assumed that anxiolytic drugs such as buspirone (1), tandospirone (2), gepirone (3) or ipsapirone (4) (Fig. 1), exert their pharmacological activity through the activation of the 5-HT 1A receptor, where they act as partial agonists.8-10) The 5-HT 1A receptor is also implicated in many other physiopathological CNS processes and conditions such as neuroprotection, schizophrenia, Parkinson's and Alzheimer's diseases, acting alone or associated with other neurotransmitter receptors, especially dopamine receptors.Long-chain arylpiperazine derivatives are one of the most important classes of 5-HT 1A ligands. In general, the arylpiperazine moiety is a good template for drugs acting on many different biological targets, especially CNS receptors.11-13) As a consequence, many compounds containing this scaffold bind with high affinity at 5-HT 1A receptors, but only a few of them also show high selectivity for 5-HT 1A over other receptors. 14)Structure-activity relationship (SAR) studies, performed with numerous generations of arylpiperazine derivatives, showed that CNS activity and both, receptor affinity and selectivity depend basically on the N-1-aryl substituent and a terminal fragment bound to the N-4 atom of the piperazine moiety by an alkyl chain. In these studies, this alkyl spacer is frequently composed of two to four methylene units. 15,16) On the other hand, the indole substructure is the basic element in a large number of biologically active natural and synthetic products. In fact, until this day, the indole motif is present in more than 400 drugs and 3000 patents.17) The range of applications for these therapeutically relevant compounds includes anti-inflammatory drugs, protein kinase C inhibitors, 5-HT agonists and antagonists, melatonin agonists and glucocorticoid receptor modulators.18) Studies on structural modifications of indolylalkylarylpiperazines carried out by Heinrich et al. 14,19) reported a high-affinity pattern for 5-HT 1A agonism and succeeded in optimizing selectivity over dopamine D 2 receptors. This structural pattern considers a C5-substituted indole ring bearing different functional groups and a parasubstituted arylpiperazine. In these studies, a four-carbon atom chain was employed as a linker of both heterocyclic moieties. On the other hand, a few studies on indolylalkylarylpiperazines containing a propyl chain as a linker have been reported regarding their 5-HT 1B/1D receptor affinity. 20,21) However, the influence of a propylic connecting chain on the affinity of this type ...

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Section: Resultssupporting

confidence: 93%

Synthesis, 5-Hydroxytryptamine1A Receptor Affinity and Docking Studies of 3-[3-(4-Aryl-1-piperazinyl)-propyl]-1H-Indole Derivatives

Pessoa‐Mahana

Núñez

Araya‐Maturana

et al. 2012

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…Derivative 1 was synthesized by the following procedure: 2.0 ml of triethylamine (1.5 g, 14.6 mmol) was added to a suspension of 2.5 g (9 mmol) of 2-(4-bromobutyl)-1,3-dioxoperhydropyrrolo[1,2-c]imidazole (Lopez-Rodriguez et al, 1996) and 2.7 g (15 mmol) of 1-(6-hydroxy-2-pyridyl)piperazine (Pavia et al, 1987) in 19 ml of acetonitrile. The mixture was refluxed for 20 to 24 h (thin-layer chromatography).…”

Section: Methodsmentioning

confidence: 99%

Design, Synthesis and Pharmacological Evaluation of 5-Hydroxytryptamine_1aReceptor Ligands to Explore the Three-Dimensional Structure of the Receptor

López-Rodrı́guez

Vicente²,

Deupí³

et al. 2002

Mol Pharmacol

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In this work, we evaluate the structural differences of transmembrane helix 3 in rhodopsin and the 5-hydroxytryptamine 1A (5-HT 1A ) receptor caused by their different amino acid sequence. Molecular dynamics simulations of helix 3 in the 5-HT 1A receptor tends to bend toward helix 5, in sharp contrast to helix 3 in rhodopsin, which is properly located within the position observed in the crystal structure. The relocation of the central helix 3 in the helical bundle facilitates the experimentally derived interactions between the neurotransmitters and the Asp residue in helix 3 and the Ser/Thr residues in helix 5. The different amino acid sequence that forms helix 3 in rhodopsin (basically the conserved Gly 3.36 Glu 3.37 motif in the opsin family) and the 5-HT 1A receptor (the conserved Cys 3.36 Thr 3.37 motif in the neurotransmitter family) produces these structural divergences. These structural differences were experimentally checked by designing and testing ligands that contain comparable functional groups but at different interatomic distance. We have estimated the position of helix 3 relative to the other helices by systematically changing the distance between the functional groups of the ligands (1 and 2) that interact with the residues in the receptor. Thus, ligand 1 optimally interacts with a model of the 5-HT 1A receptor that matches rhodopsin template, whereas ligand 2 optimally interacts with a model that possesses the proposed conformation of helix 3. The lack of affinity of 1 (K i Ͼ 10,000 nM) and the high affinity of 2 (K i ϭ 24 nM) for the 5-HT 1A receptor binding sites, provide experimental support to the proposed structural divergences of helix 3 between the 5-HT 1A receptor and rhodopsin.

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“…Biologically active compounds containing the arylpiperazine scaffold are a class of privileged structures which, due to their ability to act as dopamine and serotonine receptor ligands, hold promise as antipshychotic, antidepressant, and anxiolytic drugs (Lopez‐Rodriguez et al . ; Taverne et al . ; Gonzalez‐Gomez et al .…”

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confidence: 99%

Neuroprotective arylpiperazine dopaminergic/serotonergic ligands suppress experimental autoimmune encephalomyelitis in rats

Popović

Stanojević

Tošić

et al. 2015

Journal of Neurochemistry

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Arylpiperazine-based dopaminergic/serotonergic ligands exert neuroprotective activity. We examined the effect of arylpiperazine D 2 /5-HT 1A ligands, N-{4-[2-(4-phenyl-piperazin-1-yl)-ethyl}-phenyl]-picolinamide (6a) and N-{3-[2-(4-phenyl-piperazin-1-yl)-ethyl]-phenyl}-picolinamide (6b), in experimental autoimmune encephalomyelitis (EAE), a model of neuroinflammation. Both compounds (10 mg/kg i.p.) reduced EAE clinical signs in spinal cord homogenate-immunized Dark Agouti rats. Compound 6b was more efficient in delaying the disease onset and reducing the maximal clinical score, which correlated with its higher affinity for D 2 and 5-HT 1A receptors. The protection was retained if treatment was limited to the effector (from day 8 onwards), but not the induction phase (day 0-7) of EAE. Compound 6b reduced CNS immune infiltration and expression of mRNA encoding the proinflammatory cytokines tumor necrosis factor, IL-6, IL-1, and GM-CSF, T H 1 cytokine IFN-c, T H 17 cytokine IL-17, as well as the signature transcription factors of T H 1 (T-bet) and T H 17 (RORct) cells. Arylpiperazine treatment reduced apoptosis and increased the activation of anti-apoptotic mediators Akt and p70S6 kinase in the CNS of EAE animals. The in vitro treatment with 6b protected oligodendrocyte cell line OLN-93 and neuronal cell line PC12 from mitogen-activated normal T cells or myelin basic proteinactivated encephalitogenic T cells. In conclusion, arylpiperazine dopaminergic/serotonergic ligands suppress EAE through a direct neuroprotective action and decrease in CNS inflammation.

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Synthesis and Structure−Activity Relationships of a New Model of Arylpiperazines. 1. 2-[[4-(o-Methoxyphenyl)piperazin-1-yl]methyl]-1,3- dioxoperhydroimidazo[1,5-a]pyridine: A Selective 5-HT_1A Receptor Agonist

Cited by 61 publications

References 28 publications

Synthesis, 5-Hydroxytryptamine<sub>1A</sub> Receptor Affinity and Docking Studies of 3-[3-(4-Aryl-1-piperazinyl)-propyl]-1<i>H</i>-Indole Derivatives

Synthesis, 5-Hydroxytryptamine<sub>1A</sub> Receptor Affinity and Docking Studies of 3-[3-(4-Aryl-1-piperazinyl)-propyl]-1<i>H</i>-Indole Derivatives

Design, Synthesis and Pharmacological Evaluation of 5-Hydroxytryptamine_1aReceptor Ligands to Explore the Three-Dimensional Structure of the Receptor

Neuroprotective arylpiperazine dopaminergic/serotonergic ligands suppress experimental autoimmune encephalomyelitis in rats

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Synthesis and Structure−Activity Relationships of a New Model of Arylpiperazines. 1. 2-[[4-(o-Methoxyphenyl)piperazin-1-yl]methyl]-1,3- dioxoperhydroimidazo[1,5-a]pyridine: A Selective 5-HT1A Receptor Agonist

Cited by 61 publications

References 28 publications

Synthesis, 5-Hydroxytryptamine<sub>1A</sub> Receptor Affinity and Docking Studies of 3-[3-(4-Aryl-1-piperazinyl)-propyl]-1<i>H</i>-Indole Derivatives

Synthesis, 5-Hydroxytryptamine<sub>1A</sub> Receptor Affinity and Docking Studies of 3-[3-(4-Aryl-1-piperazinyl)-propyl]-1<i>H</i>-Indole Derivatives

Design, Synthesis and Pharmacological Evaluation of 5-Hydroxytryptamine1aReceptor Ligands to Explore the Three-Dimensional Structure of the Receptor

Neuroprotective arylpiperazine dopaminergic/serotonergic ligands suppress experimental autoimmune encephalomyelitis in rats

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Product

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Synthesis and Structure−Activity Relationships of a New Model of Arylpiperazines. 1. 2-[[4-(o-Methoxyphenyl)piperazin-1-yl]methyl]-1,3- dioxoperhydroimidazo[1,5-a]pyridine: A Selective 5-HT_1A Receptor Agonist

Design, Synthesis and Pharmacological Evaluation of 5-Hydroxytryptamine_1aReceptor Ligands to Explore the Three-Dimensional Structure of the Receptor