High Affinity and Selectivity on 5-HT1A Receptor of 1-Aryl-4-[(1-tetralin)alkyl]piperazines. 2

Perrone, Roberto; Berardi, Francesco; Colabufo, Nicola Antonio; Leopoldo, Marcello; Tortorella, Vincenzo; Fiorentini, Francesco; Olgiati, Vincenzo R.; Ghiglieri, Alberto; Govoni, Stefano

doi:10.1021/jm00006a013

Cited by 95 publications

(92 citation statements)

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“…In step b, the Grignard addition reaction afforded, in 90 % yield, the corresponding 1-cyclopropylindan-1-ol 3 which, by the action of 33 % HBr in acetic acid (step c), smoothly underwent the expected rearrangement (79 %). [36] The bromopropylidene derivative 4 was a suitable substrate to go on with the synthesis; in fact, as a 3:1 mixture of geometric isomers, it was submitted to the three steps of sequence d to yield the indanylidene compound 5 with a tethered acetamido group (63 % overall yield). In step e, trimethylsilylpolyphosphate (PPSE) promoted dehydration of the secondary amide function to generate the pivotal nitrilium ion that, by quenching onto the exocyclic olefin moiety, eventually yielded the target compound 6.…”

Section: Experimental and Computational Sectionmentioning

confidence: 99%

Quantum Chemical Modeling and Preparation of a Biomimetic Photochemical Switch

et al. 2006

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Designing and testing biomimetic switches: Multireference perturbation theory is used to model a light-driven molecular switch featuring the same photoisomerization mechanism as the chromophore of the visual pigment rhodopsin (see picture; QM/MM: quantum mechanics/molecular mechanics). By exploiting a synthetic route based on nitrilium-cation cyclization, it was shown that the designed system can indeed be prepared and characterized

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Section: Experimental and Computational Sectionmentioning

confidence: 99%

Quantum Chemical Modeling and Preparation of a Biomimetic Photochemical Switch

et al. 2006

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“…Subsequent studies, however, indicated that this compound exerted partial agonist properties at relatively high concentrations (Lanfumey et al, 1993). , an arylpiperazine derivative, has a high affinity for the 5-HT 1A receptors (K i 5 0.6 nM), but it also has a high potency for the a-1 receptor (Greuel and Glaser, 1992;Perrone et al, 1995;Raghupathi et al, 1991). In addition, NAN-190 displays partial agonist-like activity (Fornal et al, 1994;Rydelek-Fitzgerald et al, 1990;Wozniak et al, 1991).…”

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confidence: 99%

p-[18F]-MPPF: A potential radioligand for PET studies of 5-HT1A receptors in humans

Shiue

Mozley

et al. 1997

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The purpose of this study was to develop a radiopharmaceutical that could be used to selectively image 5-HT1A receptors with positron emission tomography (PET). No-carrier-added 4-(2'-methoxyphenyl)-1-[2'-(N-2"-pyridinyl)-p-[18F] fluorobenzamido]ethylpiperazine (p-[18F]-MPPF, 2) was synthesized by the nucleophilic substitution of the corresponding nitro precursor 1 with K[18F]/Kryptofix 2.2.2. in dimethyl sulfoxide (DMSO) at 140 degrees C for 20 min followed by purification with high-performance liquid chromatography (HPLC) in 10% yield in a synthesis time of 90 min from end of bombardment (EOB). Specific activity was 1-4 Ci/microM. Biodistribution studies in rats showed that the initial uptake of 2 in the brain was high (0.7% dose/g tissue at 2 min). It was then rapidly eliminated. Rates of elimination were significantly slower in brain regions with high concentrations of 5-HT1A receptors (hippocampus, cortex, and hypothalamus) than in control regions. The maximum hippocampal/cerebellar ratio was 5.6:1 at 30 min postinjection. Uptake values in serotonergic, but not in control, regions were significantly reduced by prior treatment with either (+/-)-8-OH-DPAT (2 mg/kg, i.v., 5 min prior) or WAY 100635 (1 mg/kg, i.v., 5 min prior). Radioactivity in the femur did not increase with time, suggesting that in vivo defluorination may not be the major route of metabol sm. PET studies of 2 in a monkey demonstrated selective uptake and retention of 2 in the hippocampus. The hippocampal/cerebellar ratio was 3:1 at 30 min postinjection. The ratio was reduced to 1:1 by administering (+/-)-8-OH-DPAT (2 mg/kg, i.v.) 23 min postinjection of 2. Analyses of arterial plasma by HPLC revealed that 20% of radioactivity in the plasma remained as the parent compound 2 at 30 min postinjection. The results suggest that p-[18F]-MPPF may be a useful radioligand for studying cerebral 5-HT1A receptors in humans with PET techniques.

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“…10 On the other hand, the hypothesis that the amido function does not stabilize the 5-HT 1A receptor-ligand complex has been confirmed by us in a recent work 1 on alkylamido derivatives of 1-aryl-4-[(1-tetralinyl)alkyl]piperazines, 1, where the corresponding desamido compounds 2a-c showed the highest affinity for the 5-HT 1A receptor. 11,12 So it can be stated that the amide function is not required for binding with the 5-HT 1A receptor.…”

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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

Perrone

Berardi²,

Colabufo³

et al. 1996

J. Med. Chem.

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The synthesis of 1-phenylpiperazines, linked in the alpha or beta position of the tetralin moiety on the terminal part of the N-4 alkyl chain, and their radioligand binding affinities for 5-HT(1A), 5-HT(2A), D-1, D-2, alpha1, and alpha2 receptors along with SAR studies on the 5-HT(1A) receptor are reported. Several changes have been carried out on previous structures of type 2, by inserting the alkyl chain with variable length in the alpha or beta position of the tetralin moiety and by changing the position of the methoxy group on the aromatic ring of the tetralin nucleus. The highest affinity (IC50 = 0.50 nM) and selectivity for the 5-HT(1A) receptor were showed by 1-phenylpiperazine 2a with a three-membered alkyl chain bearing a 5-methoxytetralin-1-yl ring in the omega position.

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High Affinity and Selectivity on 5-HT1A Receptor of 1-Aryl-4-[(1-tetralin)alkyl]piperazines. 2

Cited by 95 publications

References 7 publications

Quantum Chemical Modeling and Preparation of a Biomimetic Photochemical Switch

Quantum Chemical Modeling and Preparation of a Biomimetic Photochemical Switch

p-[18F]-MPPF: A potential radioligand for PET studies of 5-HT1A receptors in humans

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

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High Affinity and Selectivity on 5-HT1A Receptor of 1-Aryl-4-[(1-tetralin)alkyl]piperazines. 2

Cited by 95 publications

References 7 publications

Quantum Chemical Modeling and Preparation of a Biomimetic Photochemical Switch

Quantum Chemical Modeling and Preparation of a Biomimetic Photochemical Switch

p-[18F]-MPPF: A potential radioligand for PET studies of 5-HT1A receptors in humans

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

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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