A Series of 6- and 7-Piperazinyl- and -Piperidinylmethylbenzoxazinones with Dopamine D4 Antagonist Activity:  Discovery of a Potential Atypical Antipsychotic Agent

Abstract

As part of a program to develop dopamine D4 antagonists for the treatment of schizophrenia, we discovered a series of 6- and 7-(phenylpiperazinyl)- and -(phenylpiperidinyl)methylbenzoxazinones through mass screening of our compound library. A structure-activity relationship SAR study was carried out involving substituents on the phenyl ring, and several selective D4 antagonists were identified. The 7-substituted benzoxazinones showed more activity in neurochemical and behavioral tests than the 6-substituted series. One of the most potent and selective compounds (26) was found to have potent activity in animal tests predictive of antipsychotic activity in humans after oral administration. This paper describes the SAR of the benzoxazinone series and the preclinical characterization of 26.

The dopamine D4 receptor: biochemical and signalling properties

“…In vivo administration to monkey for cognitive and memory tests [192]; in vitro autoradiography studies [193,194] NRA 0160 0.5 Tested for antipsychotic activity in animal models [195,196] CI 1030 4.3 Tested for antipsychotic activity in animal models [195,196] A-412997 7.9 D4 receptor agonist; improves cognitive performance and stimulates motor activity in rats [197] ADHD is predominantly a condition of childhood, and is characterized by symptoms such as inattention, hyperactivity and distraction. ADHD is thought to affect up to 6% of children [141], and evidence from family data and twin studies suggests that ADHD is familial and heritable [141][142][143].…”

Phytotoxicity and Benzoxazinone Concentration in Field Grown Cereal Rye (Secale cerealeL.)

“…DIBOA and other BXs have been the focus of extensive research because they have broad biological activity, including antibacterial, antifungal, and antifeedant properties [8,21,23]. Further emphasizing the versatility of this chemistry, BXs have also been under investigation for use as pharmaceuticals [24][25][26][27]. DIBOA and its metabolites are major allelochemicals in rye, as is demonstrated by their inhibition of seedling growth in bioassays [28,29].…”

Design, Synthesis, Lipophilic Properties, and Binding Affinities of Potential Ligands in Positron Emission Tomography (PET) for Visualization of Brain Dopamine D4 Receptors

“…The inhibition curves on the different binding sites of the compounds were analyzed by nonlinear curve fitting utilizing the GraphPad Prism program. The value for the inhibition constant, K i , was calculated by using the ChengÀPrusoff equation [38].…”

“…The target compounds 6a -6f and 7a -7f were assessed for their binding affinities at human cloned D 4 , D 2 , and D 3 receptors using [ StructureÀActivity Relationships. Previous studies on N-substituted 1-arylpiperazine derivatives have revealed that polar features of the N-substituent were well tolerated with respect to D 4 -receptor affinity [38] [39]. Instead, comparing affinities of the target compounds 6a -6f and 7a -7f, characterized by a pyridinecarboxamide moiety ( Table 2), with those of the parent non-heteroaromatic compounds 1a -1f and 2a -2f (Table 1), a clear decrease in D 4 -receptor affinity was evident.…”