Tetracyclic pyridazines as potential psychopharmacological agents.
Since the Z isomer of chlorprothixene (1) is far more active than its E counterpart, it was of interest to develop a stereoselective synthesis for this class of compounds. Insertion of a benzenesulfonamido group at the peri position of a chlorprothixene precursor did affect the stereochemistry of side-chain olefin formation, but after hydrolysis attempted removal of the resulting amine led to a Widman-Stoermer cyclization to afford the corresponding tetracyclic pyridazine-containing compound (4). Since this material displayed encouraging activity in neurotransmitter uptake inhibition studies, compounds in which the sulfur bridge was replaced with an ethano bridge similar to that found in imipramine (8) and with sulfur removed (7) were also prepared. These, together with the corresponding peri amino compounds (3, 5, and 6), were tested as neurotransmitter-uptake The two bridged arylamines 3 and 6 displayed potent and selective inhibition of norepinephrine uptake both when tested in vitro and after in vivo administration. The pyridazine-containing compounds exhibited reasonable activity in vitro, but the activity was lost when they were administered in vivo. None of the compounds displayed significant ability to interfere with spiroperidol binding.
D000818:Animals; D001681:Biological Assay; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D055598:Chemical Phenomena; D002621:Chemistry; D002749:Chlorprothixene / Q000031:analogs & derivatives*; D007536:Isomerism; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D009638:Norepinephrine / Q000378:metabolism; D011619:Psychotropic Drugs; D011724:Pyridazines / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D012701:Serotonin / Q000378:metabolism; D013329:Structure-Activity Relationship
D011619:Psychotropic Drugs; D011724:Pyridazines; D012701:Serotonin; D002749:Chlorprothixene; D009638:Norepinephrine