Discovery of a New Class of Potential Multifunctional Atypical Antipsychotic Agents Targeting Dopamine D₃ and Serotonin 5-HT_1A and 5-HT_2A Receptors: Design, Synthesis, and Effects on Behavior

Abstract

Dopamine D(3) antagonism combined with serotonin 5-HT(1A) and 5-HT(2A) receptor occupancy may represent a novel paradigm for developing innovative antipsychotics. The unique pharmacological features of 5i are a high affinity for dopamine D(3), serotonin 5-HT(1A) and 5-HT(2A) receptors, together with a low affinity for dopamine D(2) receptors (to minimize extrapyramidal side effects), serotonin 5-HT(2C) receptors (to reduce the risk of obesity under chronic treatment), and for hERG channels (to reduce incidence of torsade des pointes). Pharmacological and biochemical data, including specific c-fos expression in mesocorticolimbic areas, confirmed an atypical antipsychotic profile of 5i in vivo, characterized by the absence of catalepsy at antipsychotic dose.

Arylpiperazinylalkyl derivatives of 8-amino-1,3-dimethylpurine-2,6-dione as novel multitarget 5-HT/D receptor agents with potential antipsychotic activity

“…In comparison with the first-generation antipsychotics like, e.g. haloperidol, chlorpromazine, or fluphenazine, AADs interact with many serotoninergic receptors including 5-HT 1A , 5-HT 2A , 5-HT 6 , 5HT 7 , and dopaminergic D 2 receptors 1,2 . The multiple mechanism of their action significantly reduced the range of the observed adverse effects, such as extrapyramidal symptoms 3 but those drugs did not eliminate cognitive deficits in schizophrenia.…”

“…Several series of aripiprazole analogs, e.g. quinoline-and isoquinoline -amide and sulfonamide -derivatives of long-chain arylpiperazines (LCAPs) have been explored as potential antipsychotic, antidepressant, and anxiolytic agents (Figure 1) [6][7][8] . Among the currently numerous pharmacological approaches for schizophrenia treatments, considerable attention has been focused on 5-HT 6 antagonists.…”

“…Among the currently numerous pharmacological approaches for schizophrenia treatments, considerable attention has been focused on 5-HT 6 antagonists. Because of their distribution in cerebral cortex and limbic areas, 5-HT 6 receptors were proposed to be involved in cognitive process. This modulatory activity including elevating extracellular levels of both glutamate and acetylcholine suggests potential utility for 5-HT 6 receptor antagonist in the treatment of cognitive impairments associated with schizophrenia [9][10][11] .…”

“…Because of their distribution in cerebral cortex and limbic areas, 5-HT 6 receptors were proposed to be involved in cognitive process. This modulatory activity including elevating extracellular levels of both glutamate and acetylcholine suggests potential utility for 5-HT 6 receptor antagonist in the treatment of cognitive impairments associated with schizophrenia [9][10][11] . Taking into account the above-mentioned findings, the multitarget strategy seems to be one of the most valuable approaches in the development of CNS active agents with potential antipsychotic, anxiolytic, and/or antidepressant-like activities.…”

“…For several years, our attention has been focused on the development of agents generally classified as long-chain arylpiperazines (LCAPs), containing 1,3-dimethylpurine-2,6-dione system as a terminal amide fragment, which were mainly evaluated toward 5-HT 1A , 5-HT 2A , and 5-HT 7 receptors [12][13][14][15][16][17][18] and recently also for 5-HT 6 and D 2 receptors 19,20 . Among them, several compounds containing 8-alkoxy-or 8-morpholinyl-1,3-dimethylpurine-2,6-dione moiety showed features of a 5-HT 1A /5-HT 7 or 5-HT 1A /5-HT 2A receptor ligand and produced antidepressant-and anxiolytic-like properties in behavioral tests in mice 15,18,21 .…”