Effect of Linking Bridge Modifications on the Antipsychotic Profile of Some Phthalimide and Isoindolinone Derivatives

• Published in: Journal of medicinal chemistry Vol. 39; no. 1; pp. 149 - 157
• Main Authors: Norman, Mark H, Minick, Douglas J, Rigdon, Greg C
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 05.01.1996
• Subjects: Animals; Antipsychotic Agents - chemical synthesis; Antipsychotic Agents - chemistry; Antipsychotic Agents - metabolism; Antipsychotic Agents - pharmacology; Apomorphine - pharmacology; Binding, Competitive; Biological and medical sciences; Brain - drug effects; Brain - metabolism; Clozapine - pharmacology; Haloperidol - pharmacology; Indoles - chemical synthesis; Indoles - chemistry; Indoles - metabolism; Indoles - pharmacology; Ketanserin - pharmacology; Magnetic Resonance Spectroscopy; Male; Medical sciences; Mice; Molecular Conformation; Neuropharmacology; Pharmacology. Drug treatments; Phthalimides - chemical synthesis; Phthalimides - chemistry; Phthalimides - metabolism; Phthalimides - pharmacology; Psycholeptics: tranquillizer, neuroleptic; Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D2 - metabolism; Receptors, Serotonin - metabolism; Serotonin - metabolism; Serotonin Antagonists - pharmacology; Rat; Nitrogen heterocycle; Neuroleptic; Psychotropic; Modeling; Imide; Structure activity relation; Molecular model; Antagonist; Chemical synthesis; 5-HT1A receptor; Sulfur nitrogen heterocycle; Rodentia; 5-HT2 receptor; In vitro; In vivo; Vertebrata; Biological fixation; Mammalia; D2 Dopamine receptor; Mouse; Animal; Affinity; Piperazine derivatives; Indole derivatives
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm9502201

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.