EFFECT OF LINKING BRIDGE MODIFICATIONS ON THE ANTIPSYCHOTIC PROFILE OF SOME PHTHALIMIDE AND ISOINDOLILLONE DERIVATIVES

A series of phthalimide and isoindolinone derivatives bridged to 4-(1, 2-benzisothiazo1-3-yl)-1-piperazinyl was prepared. The compounds were evaluated in vitro at dopamine D-2 and serotonin 5-HT1a and 5-HT2 rece ptors and in vivo for their ability to antagonize the apomorphine-indu ced climbing response in mice. The effects of bridge length and confor mation on the biological activity of these potential antipsychotic age nts are discussed. A four-carbon spacer provided optimal activity with in the two homologous series. Conformational investigations of the lea d compound, isoindolinone 2, were conducted in an attempt to account f or the superior activity observed for the butyl derivatives. On the ba sis of NMR and molecular modeling studies, two types of folded structu res were proposed and several conformationally restrained analogues we re synthesized. In general, restrictions incorporated within the linki ng bridge were detrimental to activity.