Structure−Activity Relationship Studies on the 5-HT<sub>1A</sub> Receptor Affinity of 1-Phenyl-4-[ω-(α- or β-tetralinyl)alkyl]piperazines. 4

Perrone, Roberto; Berardi, Francesco; Colabufo, Nicola Antonio; Leopoldo, Marcello; Tortorella, Vincenzo; Fornaretto, M. G.; Caccia, C.; McArthur, Robert A.

doi:10.1021/jm9604538

Cited by 25 publications

(27 citation statements)

References 15 publications

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“…Thus, our findings are in agreement with the hypothesis of some authors [23][24][25][26][27] that the presence of the no-pharmacophoric part is not essential for 5-HT 1A affinity. On the contrary, the isosteric change of a carbonyl group for a methylene group seems to have a negative influence on the electronic interactions for R 1 receptor binding.…”

Section: Resultssupporting

confidence: 93%

Synthesis and Structure−Activity Relationships of a New Model of Arylpiperazines. 3. 2-[ω-(4-Arylpiperazin-1-yl)alkyl]perhydropyrrolo- [1,2-c]imidazoles and -perhydroimidazo[1,5-a]pyridines: Study of the Influence of the Terminal Amide Fragment on 5-HT_1AAffinity/Selectivity

et al. 1997

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A series of new arylpiperazine derivatives 2, which are devoid of the terminal amide fragment present in related 5-HT1A ligands, was prepared and evaluated for affinity at 5-HT1A and alpha 1 receptors. All the compounds 2 demonstrated high affinity for the 5-HT1A receptor and moderate affinity for alpha 1 receptor binding sites. Structure-activity relationship (SAR) studies suggest that there is influence of electronic factors on the no-pharmacophoric part of the alpha 1 receptor site. However there is no influence of electronic interactions on the stabilization of the 5-HT1A receptor-ligand complex.

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Section: Resultssupporting

confidence: 93%

Synthesis and Structure−Activity Relationships of a New Model of Arylpiperazines. 3. 2-[ω-(4-Arylpiperazin-1-yl)alkyl]perhydropyrrolo- [1,2-c]imidazoles and -perhydroimidazo[1,5-a]pyridines: Study of the Influence of the Terminal Amide Fragment on 5-HT_1AAffinity/Selectivity

et al. 1997

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“…The synthesis of 1-phenylpiperazines, linked in the α, β or ω position of the tetralin moiety on the terminal part of the N-4 alkyl chain, and their affinities for 5-HT 1A , 5-HT 2A , D-1, D-2, α 1 and α 2 were reported by Perrone et al [113,114]. Several changes have been carried out on structures of type A (Fig.…”

Section: Mokrosz Et Al [105] Synthesised a New Set Of 4-alkyl-1-(o-mmentioning

confidence: 99%

“…The highest affinity and selectivity were shown by arylpiperazines with a three-membered alkyl chain [113,114] ( Table 17).…”

Section: Mokrosz Et Al [105] Synthesised a New Set Of 4-alkyl-1-(o-mmentioning

confidence: 99%

Derivatives as 5HT1A Receptor Ligands-Past and Present

Caliendo¹,

Santagada²,

Perissutti³

et al. 2005

CMC

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Serotonin is a neuromediator, well-know for its implication in mood regulation, anxiety, depression and, insomnia as well as in normal human function such as sleep, sexual activity and appetite. In this way, serotonin (5-hydroxytryptamine, 5-HT) is one of the most attractive targets for medicinal chemists and pharmaceutical companies. Among 5-HTRs, the 5-HT1A subtype is the best studied, and it is generally accepted that it is involved in psychiatric disorders such as anxiety and depression. Several structurally different compounds are known to bind 5-HT1A receptor sites such as aminotetralins, ergolines, arylpiperazines, indolylalkylamines, aporphines and aryloxyalkyl-amines. In this review, we report an overview of the 5-HT1A receptor ligands, belonging to different chemical classes.

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“…Compounds 3a,b and 6a (Scheme 1) were prepared by alkylating 1-(2-pyridinyl)piperazine or 2-(2-pyridyloxy)ethylamine with bromopropyl derivative 12, obtained from the aromatization of 1-(3-bromopropyl)-5-methoxy-1,2,3,4-tetrahydronaphthalene (11) 9 with N-bromosuccinimide (NBS) and triethylamine; bromoethyl derivative 13 11 and 1-(2-pyridinyl)piperazine reacted to afford compound 6a.…”

Section: Chemistrymentioning

confidence: 99%

trans-4-[4-(Methoxyphenyl)cyclohexyl]-1-arylpiperazines: A New Class of Potent and Selective 5-HT_1A Receptor Ligands as Conformationally Constrained Analogues of 4-[3-(5-Methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]-1- arylpiperazines

Perrone

Berardi²,

Colabufo³

et al. 2001

J. Med. Chem.

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The present paper concerns the influence of conformational parameters on the recognition by rat 5-HT1A receptors of derivatives 4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]-1-(2-pyridinyl)piperazine (1a) and 3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-N-[2-(2-pyridyloxy)ethyl]propanamine (3b), two highly potent and selective 5-HT1A receptor ligands. Fifteen corresponding flexible and rigid analogues were prepared following several synthetic routes and were tested in binding assays with radioligands at 5-HT1A, D2, and alpha1 receptors from rat brain membranes. Among the new derivatives emerged trans-4-[4-(3-methoxyphenyl)cyclohexyl]-1-(2-pyridinyl)piperazine (trans-8a) and trans-N-[4-(3-methoxyphenyl)cyclohexyl]-2-(2-pyridyloxy)ethylamine (trans-8b). These compounds can be considered as conformationally constrained analogues of compounds 1a and 3a, respectively. In fact, compounds trans-8a and trans-8b showed a marked enhancement in 5-HT1A receptor affinity when compared to the corresponding cis isomers. Because compound trans-8a was a potent and selective 5-HT1A ligand (K(i), nM: 5-HT1A = 0.028, D2 = 2194, alpha1 = 767), it was chosen as a lead to prepare other analogues that were tested at 5-HT1A, D2, and alpha1 receptors from rat brain membranes, showing high affinity at the 5-HT1A and selectivity vs D2 and alpha1 receptors. Selected compounds were tested for their affinity at the human cloned 5-HT1A, alpha1a, alpha1b, alpha1d receptor subtypes. They were also submitted to the [35S]GTPgammaS binding assay stimulating the 5-HT1A receptor-mediated G-protein activation, therefore behaving as full or as partial agonists. Finally, the ability of iv administration of trans-8a to induce fore-paw treading in rats was evaluated in comparison with 8-OH-DPAT. Although the affinity (K(i)) and in vitro activity (pD'2) of trans-8a at the 5-HT1A receptor were higher than those of 8-OH-DPAT, the compound was less potent than the reference standard in inducing the symptom.

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Structure−Activity Relationship Studies on the 5-HT_1A Receptor Affinity of 1-Phenyl-4-[ω-(α- or β-tetralinyl)alkyl]piperazines. 4

Cited by 25 publications

References 15 publications

Synthesis and Structure−Activity Relationships of a New Model of Arylpiperazines. 3. 2-[ω-(4-Arylpiperazin-1-yl)alkyl]perhydropyrrolo- [1,2-c]imidazoles and -perhydroimidazo[1,5-a]pyridines: Study of the Influence of the Terminal Amide Fragment on 5-HT_1AAffinity/Selectivity

Synthesis and Structure−Activity Relationships of a New Model of Arylpiperazines. 3. 2-[ω-(4-Arylpiperazin-1-yl)alkyl]perhydropyrrolo- [1,2-c]imidazoles and -perhydroimidazo[1,5-a]pyridines: Study of the Influence of the Terminal Amide Fragment on 5-HT_1AAffinity/Selectivity

Derivatives as 5HT1A Receptor Ligands-Past and Present

trans-4-[4-(Methoxyphenyl)cyclohexyl]-1-arylpiperazines: A New Class of Potent and Selective 5-HT_1A Receptor Ligands as Conformationally Constrained Analogues of 4-[3-(5-Methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]-1- arylpiperazines

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Structure−Activity Relationship Studies on the 5-HT1A Receptor Affinity of 1-Phenyl-4-[ω-(α- or β-tetralinyl)alkyl]piperazines. 4

Cited by 25 publications

References 15 publications

Synthesis and Structure−Activity Relationships of a New Model of Arylpiperazines. 3. 2-[ω-(4-Arylpiperazin-1-yl)alkyl]perhydropyrrolo- [1,2-c]imidazoles and -perhydroimidazo[1,5-a]pyridines: Study of the Influence of the Terminal Amide Fragment on 5-HT1AAffinity/Selectivity

Synthesis and Structure−Activity Relationships of a New Model of Arylpiperazines. 3. 2-[ω-(4-Arylpiperazin-1-yl)alkyl]perhydropyrrolo- [1,2-c]imidazoles and -perhydroimidazo[1,5-a]pyridines: Study of the Influence of the Terminal Amide Fragment on 5-HT1AAffinity/Selectivity

Derivatives as 5HT1A Receptor Ligands-Past and Present

trans-4-[4-(Methoxyphenyl)cyclohexyl]-1-arylpiperazines: A New Class of Potent and Selective 5-HT1A Receptor Ligands as Conformationally Constrained Analogues of 4-[3-(5-Methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]-1- arylpiperazines

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Structure−Activity Relationship Studies on the 5-HT_1A Receptor Affinity of 1-Phenyl-4-[ω-(α- or β-tetralinyl)alkyl]piperazines. 4

Synthesis and Structure−Activity Relationships of a New Model of Arylpiperazines. 3. 2-[ω-(4-Arylpiperazin-1-yl)alkyl]perhydropyrrolo- [1,2-c]imidazoles and -perhydroimidazo[1,5-a]pyridines: Study of the Influence of the Terminal Amide Fragment on 5-HT_1AAffinity/Selectivity

Synthesis and Structure−Activity Relationships of a New Model of Arylpiperazines. 3. 2-[ω-(4-Arylpiperazin-1-yl)alkyl]perhydropyrrolo- [1,2-c]imidazoles and -perhydroimidazo[1,5-a]pyridines: Study of the Influence of the Terminal Amide Fragment on 5-HT_1AAffinity/Selectivity

trans-4-[4-(Methoxyphenyl)cyclohexyl]-1-arylpiperazines: A New Class of Potent and Selective 5-HT_1A Receptor Ligands as Conformationally Constrained Analogues of 4-[3-(5-Methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]-1- arylpiperazines