Cyclic Benzamides as Mixed Dopamine D2/Serotonin 5-HT2 Receptor Antagonists: Potential Atypical Antipsychotic Agents

Abstract

A series of novel 4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl) cyclic amides was prepared and evaluated as potential antipsychotic agents. The target compounds were examined in vitro for their binding affinities to the dopamine D2, serotonin 5-HT2, and serotonin 5-HT1a receptors and in vivo for their ability to antagonize the apomorphine-induced climbing response in mice. Derivatives that exhibited good D2/5-HT2 selectivity in vitro and good potency in vivo were selected for further evaluation in tests designed to assess their potential extrapyramidal side effect liability. Structural modifications discussed herein focus on the bicyclic amide subunit leading to the preparation of a variety of heterocyclic ring systems (i.e., phthalimide, isoindolinone, isoquinolinone, benzazepinone, indazolone, phthalazinone, 4-methyl phthalazinone, benzisothiazolone 1,1-dioxide, benzotriazinone, homophthalimide, benzisothiazolone, phthalazinedione, quinazoline, and saturated phthalazinones). The potency and selectivity within this series was found to be dependent on ring size, nature of the covalent linking unit, relative position of the functional groups, degree of unsaturation, and relative stereochemistry. In general, the cyclic benzamides examined in this investigation exhibited receptor binding activities indicative of potential atypical antipsychotic agents. Several of these derivatives possessed in vivo activities that suggest they would be useful in the treatment of schizophrenia and would have a low propensity to induce extrapyramidal side effects. Two potent analogues were identified and selected for further evaluation: 2-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl)-1-isoind olinone (31) and (+-)-cis-2-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)-butyl)- 4a,5,6,7,8,8a-hexahydro-1(2H)-phthalazinone hydrochloride (52).

Synthesis and Nootropic Activity of Some 2,3‐Dihydro‐1H‐isoindol‐1‐one Derivatives Structurally Related with Piracetam

“…Some isoindolinones have been described as anxiolytics and reverse transcriptase inhibitors [8] [9], antipsychotics [10], tranquilizing agents and sedatives [11], antimicrobials [12], antitumor agents [13], and 5-HT 2C antagonists [14]. Therefore, taking in count that isoindolinone has the 2-oxopyrrolidine moiety in its structure, and that, among the large number of structurally related molecules to piracetam, there are no nootropic isoindolones, in the present work we synthesized three isoindolinones structurally related with piracetam and tested their ability to revert the scopolamineinduced amnesia in mice.…”

Phthalazin-1(2H)-one as a remarkable scaffold in drug discovery

“…They were M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT 4 developed as enzyme inhibitors, such as aldose reductase (AR) inhibitors [7], poly(ADP-ribose)polymerase (PARP) inhibitors [8] or phosphodiesterase (PDE) inhibitors [9], as ligands acting at G protein-coupled receptors (GPCRs), in particular histamine receptors [10], adrenoceptors [11], dopamine/serotonin receptors [12], or adenosine receptors [13], or even as modulators of ion channel-coupled receptors [14] or ligands for nuclear receptors [15]. Thus, phthalazinone derivatives have a wide variety of biological properties like antidiabetic [16], anticancer [17], antiasthmatic [18], anti-inflammatory and analgesic [19], antihistaminic [20], antihypertensive and antithrombotic [21], anticonvulsant [22], antimicrobial [23], antiviral [24], antiparasitic [25], as well as antidepressant and antipsychotic activities [26,12]. Their use as diagnostic agents [27] or even as herbicides [28] was also described.…”

Design, Synthesis, Characterization, and Antimicrobial Screening of Novel Indazole Bearing Oxadiazole Derivatives

“…Natural products bearing an indazole structure are rare , and at present only, two examples are known: nigellicine and nigellidine . However, many synthetic indazoles are known, and a number are important because of their pharmaceutical activity; some act as dopamine antagonists, anti‐inflammatory, and analgesic or antipyretic agents . Others also exhibit CNS activity , and 6‐nitroindazoles and 7‐nitroindazoles are used to study the behavior of nitric oxide in vivo .…”