Synthesis and 5-HT-3 receptor binding activity of 5-[125I]iodo-2,3-dimethoxy-N-(1-azabicyclo[2.2.2]oct-3-yl)benzamide and its 5-halogen-2-alkoxyl homologues

Hewlett, William A.; Schmidt, D. E.; Mason, N. Scott; Trivedi, Bakula; Ebert, M. H.

doi:10.1016/s0223-5234(97)81676-5

Cited by 8 publications

(3 citation statements)

References 32 publications

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“…The most potent substituted benzamides in this study ( Fig. 1; compounds 1-6) all share the 3-quinuclidinyl moiety of zacopride, and differ only in the nature and position of their aromatic substituents (de Paulis et al 1997;Hewlett et al 1998). …”

Section: Discussionmentioning

confidence: 85%

Discrimination in 5-HT 3 receptor binding in murine brain and cultured cell preparations

Zhang

Trivedi

Schmidt

et al. 2002

Naunyn-Schmiedeberg's Archives of Pharmacology

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One-hundred ninety-one ligands were screened at 5-HT(3) receptors in membranes from rat brain and NCB20 cells for their ability to displace the selective, high-affinity 5-HT(3) receptor antagonist, [(125)I]DAIZAC ([(125)I]( S)-5-chloro-3-iodo-2-methoxy- N-(1-azabicyclo[2.2.2]oct-3-yl)benzamide). Thirty-seven compounds having structures related to benzamide, dibenzepine, serotonin, phenylbiguanide, or arylpiperzine were selected for more extensive displacement studies in membranes from rat and mouse brains, from two cultured cell preparations expressing heteromeric mouse-derived 5-HT(3) receptor proteins (NCB20 and NG108-15 cell lines), and from recombinant Sf9 cells expressing homomeric 5-HT(3A) receptors. [(125)I]DAIZAC bound specifically to a single site in each of the five tissue preparations with high affinity ( K(D) 0.12-0.19 nM). The densities of [(125)I]DAIZAC-labeled 5-HT(3) receptors were 7.4-7.5 fmol/mg protein in membranes from murine brain, and 38, 99, and 1588 fmol/mg protein in membranes from cultured NCB20, NG108-15, and recombinant Sf9 cells, respectively. The affinity of substituted benzamides ( n=10) was similar in all five tissue preparations. The affinity of dibenzepines ( n=17) was significantly higher in membranes from cultured cells as compared to membranes from rat and mouse brain, but similar in the two brain membrane preparations, and in each of the cultured cell membrane preparations. Serotonin-, phenylbiguanide-, and quipazine-analogs ( n=10), which typically function as 5-HT (5-hydroxytryptamine) agonists, exhibited significantly higher apparent p K(i) values in membranes from rat brain and Sf9 recombinant cells than in membranes from the three preparations expressing heteromeric mouse-derived 5-HT(3) receptor proteins ( F=7.52, P<0.001). These findings confirm that there are both species and cell-type dependent differences in binding to 5-HT(3) receptors, and that care must be taken when comparing results between experimental paradigms that utilize different sources of 5-HT(3) receptors.

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Section: Discussionmentioning

confidence: 85%

Discrimination in 5-HT 3 receptor binding in murine brain and cultured cell preparations

Zhang

Trivedi

Schmidt

et al. 2002

Naunyn-Schmiedeberg's Archives of Pharmacology

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“…Reactions were monitored by thin-layer chromatography (TLC) analysis. The following compounds were prepared according to literature procedures: 2-hydroxy-3-methoxybenzoic acid, methyl ester, and oxazoline 14 …”

Section: Methodsmentioning

confidence: 99%

Synthesis of the Benzophenone Fragment of Balanol via an Intramolecular Cyclization Event

et al. 2000

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Studies are reported on the use of either a 7-exo radical cyclization or an intramolecular Heck reaction as the key step for the construction of the benzophenone fragment of the PKC inhibitor, balanol. Whereas, the former approach was unsuccessful, the Heck reaction proved to be viable for the coupling of two fully functionalized aryl subunits affording regioselectively a biaryl seven-membered lactone with an exocyclic alkene as the major component, in contrast to the competing eight-membered ring lactone. Hydrolysis of the lactone followed by oxidative cleavage of the alkene with ruthenium tetraoxide completed this short synthesis of the benzophenone unit.

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“…1). [1][2][3][4][5][6][7][8] Aminoquinuclidine has also been identified in a compound, PNU-282987 (4), 9 featuring a7 nicotinic acetylcholine receptor agonist activity (Fig. 1), and in compounds showing butyrylcholinesterase inhibition.…”

Section: Introductionmentioning

confidence: 99%

Unexpected rearrangement of enantiomerically pure 3‐aminoquinuclidine as a simple way of preparing diastereomeric octahydropyrrolo[2,3‐c]pyridine derivatives

Goljer¹,

Molinari²,

He³

et al. 2008

Chirality

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Reaction of (S)- or (R)-3-aminoquinuclidine with 2-chloropyrimidine or 2-bromopyrimidine led to an unexpected formation of both cis- and trans-octahydropyrrolo [2,3]pyridine derivatives. A single-step synthesis of two of the four stereoisomers of these octahydropyrrolo[2,3]pyridine derivatives provides a convenient way of generating stereochemically defined isomers. Optimization of reaction conditions was carried out by (1)H NMR monitoring. The relative and absolute stereochemistry of all four stereoisomers was determined by a combination of (1)H, (13)C, and (15)N NMR spectroscopy and vibrational circular dichroism spectroscopy.

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Synthesis and 5-HT-3 receptor binding activity of 5-[125I]iodo-2,3-dimethoxy-N-(1-azabicyclo[2.2.2]oct-3-yl)benzamide and its 5-halogen-2-alkoxyl homologues

Cited by 8 publications

References 32 publications

Discrimination in 5-HT 3 receptor binding in murine brain and cultured cell preparations

Discrimination in 5-HT 3 receptor binding in murine brain and cultured cell preparations

Synthesis of the Benzophenone Fragment of Balanol via an Intramolecular Cyclization Event

Unexpected rearrangement of enantiomerically pure 3‐aminoquinuclidine as a simple way of preparing diastereomeric octahydropyrrolo[2,3‐c]pyridine derivatives

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