Source:http://linkedlifedata.com/resource/pubmed/id/12408724
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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
23
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| pubmed:dateCreated |
2002-10-31
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| pubmed:abstractText |
A series of new pyridobenzodiazepines with variation of the basic side chain were synthesized and evaluated for their binding to D(4.2), D(2L), and 5-HT(2A) receptors in comparison with clozapine, haloperidol, and two parent compounds previously described, 8-chloro-6-(4-methyl-1-piperazinyl)-11H-pyrido[2,3-b][1,4]benzodiazepine (8) and 8-methyl-6-(4-methyl-1-piperazinyl)-11H-pyrido[2,3-b][1,4]benzodiazepine (9). In the piperazine series, replacing the N-methyl group by a N-phenyl moiety (15-17, 30-32) provided a dramatic decrease of affinity for all receptors (K(i) > 1000 nM). A N-cyclohexyl group (20, 35) restored some affinity. Compounds with a N-benzyl (18, 33) or N-phenethyl side chain (19, 34) had significant affinities at D(4.2) and 5-HT(2A) receptors. Homologation of the piperazine nucleus (29, 44) led to a significant decrease of the affinity at all receptors investigated. In the 4-aminopiperidine series, N-methyl derivatives (21, 36) possessed less affinity in comparison with the N-methylpiperazine analogues (8, 9) while the N-benzyl congeners (22, 37) showed similar affinities. The rigidification of piperidine nucleus as obtained in azabicyclo[3.2.1]octane derivatives (23, 38) involved a slight reduction of the affinity at D(4.2) and 5-HT(2A) receptors while the affinity at D(2L) receptors was dramatically increased. The introduction of N-substituted aminoalkylamines to replace N-methylpiperazine generally led to a significant decrease in the affinity for D(4.2) receptors but some of these molecules (24, 25, 41) presented a significant 5-HT(2A) binding affinity. The presence of a more flexible side chain induced an increased conformational freedom. Consequently, the preferential position of the distal nitrogen or its basicity in piperazine derivatives was greatly modified. 19 with a high D(4.2) and 5-HT(2A) affinity (K(i) = 40 and 103 nM, respectively) did not induce cataleptic phenomenon in the paw test in rats but significantly reduced the immobility time in Porsolt's test in mice suggesting antidepressant properties.
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| pubmed:language |
eng
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| pubmed:journal | |
| pubmed:citationSubset |
IM
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| pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Amines,
http://linkedlifedata.com/resource/pubmed/chemical/Antidepressive Agents,
http://linkedlifedata.com/resource/pubmed/chemical/Benzodiazepines,
http://linkedlifedata.com/resource/pubmed/chemical/DRD4 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Dopamine Agents,
http://linkedlifedata.com/resource/pubmed/chemical/Drd4 protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Drd4 protein, rat,
http://linkedlifedata.com/resource/pubmed/chemical/Piperazines,
http://linkedlifedata.com/resource/pubmed/chemical/Piperidines,
http://linkedlifedata.com/resource/pubmed/chemical/Receptor, Serotonin, 5-HT2A,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Adrenergic, alpha-1,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Dopamine D2,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Dopamine D4,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Serotonin,
http://linkedlifedata.com/resource/pubmed/chemical/Serotonin Agents,
http://linkedlifedata.com/resource/pubmed/chemical/dopamine D2L receptor
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| pubmed:status |
MEDLINE
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| pubmed:month |
Nov
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| pubmed:issn |
0022-2623
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| pubmed:author | |
| pubmed:issnType |
Print
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| pubmed:day |
7
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| pubmed:volume |
45
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| pubmed:owner |
NLM
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| pubmed:authorsComplete |
Y
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| pubmed:pagination |
5136-49
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| pubmed:dateRevised |
2008-11-21
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| pubmed:meshHeading |
pubmed-meshheading:12408724-Amines,
pubmed-meshheading:12408724-Animals,
pubmed-meshheading:12408724-Antidepressive Agents,
pubmed-meshheading:12408724-Benzodiazepines,
pubmed-meshheading:12408724-Catalepsy,
pubmed-meshheading:12408724-Cell Line,
pubmed-meshheading:12408724-Dopamine Agents,
pubmed-meshheading:12408724-Female,
pubmed-meshheading:12408724-Humans,
pubmed-meshheading:12408724-Mice,
pubmed-meshheading:12408724-Molecular Conformation,
pubmed-meshheading:12408724-Piperazines,
pubmed-meshheading:12408724-Piperidines,
pubmed-meshheading:12408724-Radioligand Assay,
pubmed-meshheading:12408724-Rats,
pubmed-meshheading:12408724-Rats, Wistar,
pubmed-meshheading:12408724-Receptor, Serotonin, 5-HT2A,
pubmed-meshheading:12408724-Receptors, Adrenergic, alpha-1,
pubmed-meshheading:12408724-Receptors, Dopamine D2,
pubmed-meshheading:12408724-Receptors, Dopamine D4,
pubmed-meshheading:12408724-Receptors, Serotonin,
pubmed-meshheading:12408724-Serotonin Agents,
pubmed-meshheading:12408724-Structure-Activity Relationship
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| pubmed:year |
2002
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| pubmed:articleTitle |
New pyridobenzodiazepine derivatives: modifications of the basic side chain differentially modulate binding to dopamine (D(4.2), D(2L)) and serotonin (5-HT(2A)) receptors.
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| pubmed:affiliation |
Natural and Synthetic Drugs Research Center, Laboratory of Medicinal Chemistry, University of Liège, avenue de l'Hôpital 1 (B36), Belgium. JF.Liegeois@ulg.ac.be
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| pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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