Pharmacologic Characterization of a Novel Non-Benzodiazepine Selective Anxiolytic, DN-2327

Wada, Takeo; Nakajima, Ryoko; Kurihara, Eiji; Narumi, Shigehiko; Masuoka, Yutaka; Goto, Giichi; Saji, Yoshiaki; Fukuda, Naohisa

doi:10.1016/s0021-5198(19)43043-6

Cited by 7 publications

(10 citation statements)

References 15 publications

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“…These data indicate that the relative potency of DN-2327 and alprazolam in disrupting psychomotor–cognitive performance is somewhat less than 16:1. The present results demonstrating the psychomotor impairing effects of DN-2327 in humans contrast with preclinical data, which suggest that DN-2327 produces limited myorelaxation and locomotor depression (Wada et al, 1989) and suggest possible species differences in the behavioral pharmacology of DN-2327.…”

Section: Discussioncontrasting

confidence: 84%

“…DN-2327, (2-(7-chloro-1,8-naphthyridin-2-yl)-3-[(1.4-dioxa-8-azaspiro[4.5]dec-8-yl)-carbonylmethyl]isoindolin-1-one) a novel nonbenzodiazepine compound that is under development for the treatment of generalized anxiety disorder, is believed to produce its pharmacological effects via the gamma-aminobutyric acid (GABA) benzodiazepine chloride channel receptor complex (Wada et al, 1989). The pharmacological profile of DN-2327 is similar in many respects to that of the classic benzodiazepine anxiolytics and hypnotics.…”

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confidence: 99%

“…The pharmacological profile of DN-2327 is similar in many respects to that of the classic benzodiazepine anxiolytics and hypnotics. Preclinical studies have shown that DN-2327 produces anticonvulsant, anticonflict, anxiolytic, taming, and discriminative stimulus effects that are generally similar to benzodiazepines (Wada & Fukuda, 1991a, 1991b, 1992, 1993; Wada et al, 1989), and behavioral effects of DN-2327 are antagonized by the benzodiazepine antagonist flumazenil (Wada & Fukuda, 1991a, 1991b).…”

mentioning

confidence: 99%

“…DN-2327 has been characterized as a partial benzodiazepine agonist on the basis of its ability to attenuate diazepam-induced motor incoordination in rats and mice (Wada & Fukuda, 1991b) and diazepam-induced potentiation of pentobarbital effects in mice (Wada & Fukuda, 1991b). Biochemical studies with DN-2327 found that, unlike diazepam, the binding of DN-2327 to benzodiazepine receptors was not enhanced by GABA (i.e., unaltered GABA ratio; Wada et al, 1989). Although DN-2327 was equipotent to diazepam in rodent anticonflict tests (Wada & Fukuda, 1991a; Wada et al, 1989), diazepam but not DN-2327 produced myorelaxation, locomotor depression, and potentiation of pentobarbital- and ethanol-induced loss of righting reflex (Wada et al, 1989).…”

mentioning

confidence: 99%

“…Biochemical studies with DN-2327 found that, unlike diazepam, the binding of DN-2327 to benzodiazepine receptors was not enhanced by GABA (i.e., unaltered GABA ratio; Wada et al, 1989). Although DN-2327 was equipotent to diazepam in rodent anticonflict tests (Wada & Fukuda, 1991a; Wada et al, 1989), diazepam but not DN-2327 produced myorelaxation, locomotor depression, and potentiation of pentobarbital- and ethanol-induced loss of righting reflex (Wada et al, 1989). Finally, DN-2327, unlike diazepam, did not affect acquisition in a passive avoidance paradigm or performance in a food-reinforced delayed alternation procedure (Wada & Fukuda, 1992).…”

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confidence: 99%

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Alprazolam and DN-2327 (Pazinaclone) in humans: Psychomotor, memory, subjective, and reinforcing effects.

Mumford¹,

Rush²,

Griffiths³

1995

Experimental and Clinical Psychopharmacology

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The psychomotor, memory, subjective, and reinforcing effects of DN-2327 (DN), a novel partial agonist at benzodiazepine receptors, were compared with those of alprazolam (AL) in 14 men with histories of sedative drug abuse. Placebo, DN (8,16, and 32 mg), and AL (0.5,1.0, and 2.0 mg) were administered orally in a randomized, double-blind, cross-over design. DN and AL produced similar maximal impairment on psychomotor and memory performance. AL produced greater increases in participant ratings of sedation and a variety of somatic symptoms that were absent following DN. Abuse liability measures showed both drugs increased liking and good effects and were categorized by participants as sedative-hypnotics; however, 2 of 3 indirect and 1 direct measure of drug reinforcement were greater with AL than with DN. The dissociation between psychomotormemory performance effects and various subjective effects demonstrates a novel pharmacological profile of DN.

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Section: Discussioncontrasting

confidence: 84%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Alprazolam and DN-2327 (Pazinaclone) in humans: Psychomotor, memory, subjective, and reinforcing effects.

Mumford¹,

Rush²,

Griffiths³

1995

Experimental and Clinical Psychopharmacology

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Amidation and Intramolecular Aza‐Michael Reaction: One‐Pot Synthetic Strategy of Isoindolinones

Ali

Bera²,

Molla

et al. 2021

ChemistrySelect

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Herein, we report one-pot Cu(I) catalyzed open flask synthetic strategy of 3-substituted N-pyridinyl isoindolinones from alkyl (E)-3-(2-formylphenyl)acrylate by oxidative amidation and intramolecular aza-Michael reaction using cheap air stable Cu(I) single catalyst. We have also established a synthetic route of Naryl substituted isoindolinones with acid-amine coupling reaction of (E)-2-(3-alkoxy-3-oxoprop-1-en-1-yl)benzoic acid followed by aza-Michael reactions. Unexpected synthetic route of N-(1H-inden-1-yl)pyridin-2-amine derivatives have been documented from the same precursors using Cu(I) catalyst.

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Divergent Reactivity of 1,2,3-Benzotriazin-4(3H)-ones: Photocatalytic Synthesis of 3-Substituted Isoindolinones Achieved through a Nitrogen-Mediated Hydrogen Atom Shift

Bokosi,

Shiels,

Richardson

et al. 2024

J. Org. Chem.

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A regioselective visible-light-mediated denitrogenative alkene insertion of 1,2,3-benzotriazin-4(3H)-ones was developed to access 3-substituted isoindolinones, an important structural motif present in many biologically active molecules and natural products. Notably, divergent reactivity was achieved by switching from reported nickel catalysis (where C3-substituted 3,4dihydroisoquinolin-1(2H)-ones form) to photocatalysis, where photocatalytic denitrogenation and a subsequent nitrogen-mediated hydrogen atom shift lead to exclusive 3-substituted isoindolinone formation. The developed photocatalytic reaction is compatible with activated terminal alkenes and cyclic α,β-unsaturated esters and ketones, with wide functional group tolerance for Nsubstitution of the 1,2,3-benzotriazin-4(3H)-ones. The utility of this procedure is highlighted by a gram-scale synthesis and postsynthetic amidation. To understand the origin of this unique product selectivity, experimental and computational mechanistic studies were performed.

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Pharmacologic Characterization of a Novel Non-Benzodiazepine Selective Anxiolytic, DN-2327

Cited by 7 publications

References 15 publications

Alprazolam and DN-2327 (Pazinaclone) in humans: Psychomotor, memory, subjective, and reinforcing effects.

Alprazolam and DN-2327 (Pazinaclone) in humans: Psychomotor, memory, subjective, and reinforcing effects.

Amidation and Intramolecular Aza‐Michael Reaction: One‐Pot Synthetic Strategy of Isoindolinones

Divergent Reactivity of 1,2,3-Benzotriazin-4(3H)-ones: Photocatalytic Synthesis of 3-Substituted Isoindolinones Achieved through a Nitrogen-Mediated Hydrogen Atom Shift

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