Structure-activity relationships of 2-aryl-2,5-dihydropyridazino [4,3-b]indol-3(3H)-ones at the benzodiazepine receptor.
A large series of 2-aryl-2,5-dihydropyridazino[4,3-b]indol-3(3H)ones (PIs) carrying properly selected substituents at the indole and N2-phenyl rings was prepared and tested as central benzodiazepine receptor (BZR) ligands and potential (anti)convulsant agents. Stereoelectronic requirements for high receptor affinity were detected by means of 2-D and 3-D QSAR analyses. BZR affinities and pharmacological profiles of the compounds were examined in comparison with some other pyridazinoindolones recently described by us and with pyrazoloquinoline (PQ) analogues. An anticonvulsant activity greater than PQs was generally observed for PIs. Notably, in the test of audiogenically induced seizures, one compound showed a potency comparable to that of diazepam.
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Dipartimento Farmacochimico, Università di Bari, Italy.
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De Sarro
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D000818:Animals; D000927:Anticonvulsants / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology*; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D006860:Hydrogen Bonding; D007211:Indoles / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008811:Mice, Inbred DBA; D008958:Models, Molecular; D010433:Pentylenetetrazole / Q000494:pharmacology; D011724:Pyridazines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism*; D012044:Regression Analysis; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy; D013329:Structure-Activity Relationship
C105403:2-(4-bromophenyl)-2,5-dihydropyridazino(4,3-b)indol-3(3H)-one; C105404:2-(4-chlorophenyl)-5-methyl-2,5-dihydropyridazino(4,3-b)indol-3(3H)-one; D000927:Anticonvulsants; D007211:Indoles; D011724:Pyridazines; D011963:Receptors, GABA-A; D010433:Pentylenetetrazole