Effect of linking bridge modifications on the antipsychotic profile of some phthalimide and isoindolinone derivatives.
A series of phthalimide and isoindolinone derivatives bridged to 4-(1,2-benzisothiazol-3-yl)-1-piperazinyl was prepared. The compounds were evaluated in vitro at dopamine D2 and serotonin 5-HT1a and 5-HT2 receptors and in vivo for their ability to antagonize the apomorphine-induced climbing response in mice. The effects of bridge length and conformation on the biological activity of these potential antipsychotic agents are discussed. A four-carbon spacer provided optimal activity within the two homologous series. Conformational investigations of the lead compound, isoindolinone 2, were conducted in an attempt to account for the superior activity observed for the butyl derivatives. On the basis of NMR and molecular modeling studies, two types of folded structures were proposed and several conformationally restrained analogues were synthesized. In general, restrictions incorporated within the linking bridge were detrimental to activity.
Norman
M H
MH
Division of Chemistry, Glaxo Wellcome Inc., Research Triangle Park, North Carolina 27709, USA.
Minick
D J
DJ
Rigdon
G C
GC
D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001058:Apomorphine / Q000494:pharmacology; D001667:Binding, Competitive; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D003024:Clozapine / Q000494:pharmacology; D006220:Haloperidol / Q000494:pharmacology; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D007650:Ketanserin / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008968:Molecular Conformation; D010797:Phthalimides / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D011985:Receptors, Serotonin / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D012702:Serotonin Antagonists / Q000494:pharmacology
D014150:Antipsychotic Agents; D007211:Indoles; D010797:Phthalimides; D017448:Receptors, Dopamine D2; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D012701:Serotonin; D007650:Ketanserin; D003024:Clozapine; D006220:Haloperidol; D001058:Apomorphine