Thienylpyrazoloquinolines: potent agonists and inverse agonists to benzodiazepine receptors

Takada, Susumu; Shindo, Hitoshi; Sasatani, Takashi; Chomei, Nobuo; Matsushita, Akira; Eigyo, Masami; Kawasaki, Kazuo; Murata, Shunji; Takahara, Yukio; Shintaku, Haruyuki

doi:10.1021/jm00117a012

Cited by 32 publications

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“…The role of the hydrogen atom at the 5-position of the pyrazolo[4,3- c ]quinolines as the hydrogen bond donor is well-defined for high affinity to BZ receptors. ,, We thought that an imidazo[4,5- c ]quinoline might be a bioisostere of an pyrazolo[4,3- c ]quinoline because a tautomer with a hydrogen atom at the 5-position of the former may exist when it interacts with the receptor protein. Compounds initially synthesized in this series exhibited a broad range of affinities ( K i = 1.7−270 nM) in comparison to their corresponding pyrazoloquinolines ( K i = 0.22−0.83 nM) as shown in Table .…”

Section: Resultsmentioning

confidence: 99%

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Synthesis and Structure−Activity Relationships of Fused Imidazopyridines: A New Series of Benzodiazepine Receptor Ligands

et al. 1996

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2-Arylimidazo[4,5-c]quinolines and analogous fused imidazopyridines were synthesized and evaluated as benzodiazepine receptor ligands. Affinity to the receptors was greatly affected by the bulkiness of the aryl group at the 2-position, compared to the pyrazoloquinolines such as CGS-9896. Derivatives with an isoxazole moiety at the 2-position showed high binding affinity and in vivo activity. In the imidazo[4,5-c]quinoline series, substitution at the 6-position decreased or abolished activity. Most derivatives with an unsubstituted isoxazolyl group showed antagonist or inverse agonist activity except for the 7-halo analogues, which exhibited agonist activity. On the other hand, 5-methylisoxazol-3-yl or 3-methylisoxazol-5-yl derivatives generally exhibited agonist activity. A similar substitution effect on the isoxazole moiety was observed in the imidazopyridines fused with a nonaromatic ring. From the detailed pharmacological evaluation, S-8510, 2-(3-isoxazolyl)-3,6,7,9-tetrahydroimidazo[4,5-d]pyrano++ +[4,3-b]pyridine monophosphate, possessing weak inverse agonist activity was selected as a therapeutic candidate for the treatment of some symptoms of senile dementia.

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Section: Resultsmentioning

confidence: 99%

“…This was measured by displacement of [ 3 H]diazepam to receptor preparation obtained from the cerebral cortex of Wistar rats. The procedure is given in our previous paper …”

Section: Pharmacological Methodsmentioning

confidence: 99%

Synthesis and Structure−Activity Relationships of Fused Imidazopyridines: A New Series of Benzodiazepine Receptor Ligands

et al. 1996

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“…NMR (CD3COCD3): = 0.80-1.90 (m, 12 H, CH2), 2.09 (s, 3 H, CCH3), 2.20 (t, J = 7 Hz, 2 H, COCH2), 3.08-3.71 (m, 4 H, CONCH2), 4.01 (t, J = 7 Hz, 2 H, NCH2), 6.69-7.5 (m, 7 H, ArH), 7.95 (s, 1 H, OH), 9.00 (s, 1 , OH). NMR (CD3COCD3): = 0.85-1.88 (m, 6 H, CH2), 1.90-2.31 (m, 2 H, COCH2), 2.10 (s, 3 H, CCH3), 2.86 (s, 1 , NH), 4.03 (t, J = 7 Hz; 2 H, NCH2), 4.39 (t, J = 3 Hz, 2 H, NHCH2), 6.77-7.49 (m, 12 H, ArH), 7.70 (s, 1 H, OH), 8.74 (s, 1 , OH). Anal.…”

Section: Methodsmentioning

confidence: 99%

1-(Aminoalkyl)-2-phenylindoles as novel pure estrogen antagonists

Angerer

Knebel²,

Kager³

et al. 1990

J. Med. Chem.

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A number of 1-(omega-aminoalkyl)-5-hydroxy-2-(4-hydroxyphenyl)indoles were synthesized and studied for their binding affinities for the calf uterine estrogen receptor and estrogen antagonistic activities. Highest binding affinities were found with derivatives bearing a methyl group in position 3 and a hexamethylene chain between the indole and amino nitrogen atoms. Values for relative binding affinity (RBA) are between 20 and 30 for derivatives 5b, 5c, 5f, and 5h (17 beta-estradiol = 100). In the mouse uterine weight test, no significant agonistic (estrogenic) activity was observed up to a daily dose of 125 micrograms/animal, except for derivatives 5c, 5j, and 5l. 2-Phenylindoles with amino (5b), pyrrolidino (5f), piperidino (5h), and morpholino (5k) groups as the amino function completely suppressed estrone-stimulated uterine growth as a dose of 125 micrograms/animal (100% antagonism). Therefore, these derivatives can be considered as first examples of nonsteroidal pure antiestrogens.

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“… 12 The 3-bromothienothiophene needs to be prepared by annelation of a thiophene ring to a 3-brominated thiophene 13 because bromination of thienothiophene would result in a different substitution pattern. 14 Also, thiophenes substituted with pyrazoloquinolines at the 3-position, which were found to be antagonists of benzodiazepine receptors, 15 were synthesized from building blocks that already carry a substituent at the 3-position. 15 Imidazopyridines substitued with nitrogen at the 2-position, similar to compounds 17 and 18 , are motifs in kallikrein-7 inhibitors.…”

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“… 14 Also, thiophenes substituted with pyrazoloquinolines at the 3-position, which were found to be antagonists of benzodiazepine receptors, 15 were synthesized from building blocks that already carry a substituent at the 3-position. 15 Imidazopyridines substitued with nitrogen at the 2-position, similar to compounds 17 and 18 , are motifs in kallikrein-7 inhibitors. 16 The 2-aminoimidazopyridine unit was synthesized in a four-step synthesis by annelation of the imidazole ring to a pyridine.…”

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confidence: 99%