Identification of a butyrophenone analog as a potential atypical antipsychotic agent: 4-[4-(4-Chlorophenyl)-1,4-diazepan-1-yl]-1-(4-fluorophenyl)butan-1-one

Ablordeppey, Seth Y.; Altundaş, Ramazan; Bricker, Barbara A.; Xiao-lin, Zhu; Kumar, Eyunni V.K. Suresh; Jackson, Tanise; Khan, Abdul Rahman; Roth, Bryan L.

doi:10.1016/j.bmc.2008.06.030

Cited by 42 publications

(49 citation statements)

References 46 publications

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“…1,5,4 Modifications of the piperidine ring resulting in D 2 receptor binding profiles that are similar or better than haloperidol and which could not form toxic pyridinium metabolites, were also identified. 4,6,7 These studies have indicated that adding an ethylene bridge to the piperidine moiety to form a tropane analog, maintained or increased affinity for the D 2 receptor subtype.…”

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confidence: 99%

“…5,9 Thus, it was of interest in this study, to further test the hypothesis that moderation of the binding affinity at the D 2 receptor could attenuate catalepsy in the tropane analogs of haloperidol. To test this hypothesis, we modified the fluorobutyrophenone moiety while replacing the piperidinol with 3-tropanol to obtain compounds 2-10 as shown in Fig 2 and then evaluated their binding affinities at receptors associated with antipsychotic activity, i.e., D 1 and D 2 -like receptors, 5-HT 1A R, 5-HT 2A R and 5-HT 7 R (Table 1).…”

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confidence: 99%

“…14,15 Thus, in this study, the reversal of APO-induced climbing was assessed in Swiss Webster mice given 1.5 mg/kg of APO in a manner consistent with previous reports. 1,5 Doses were expressed as the free base for haloperidol and apomorphine, and as the HCl salt for compounds 8 and 9 and were given in a volume of 10 mL/kg for the highest dose given by intraperitoneal (ip) injection, except for APO, which was given by subcutaneous (sc) injection. Five mice were each dosed, at various concentrations with compounds 8 or 9 , then 30 min later with APO (1.5 mg/kg).…”

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Further evaluation of the tropane analogs of haloperidol

Sampson

Bricker

Xiao-lin

et al. 2014

Bioorganic & Medicinal Chemistry Letters

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Previous work from our labs has indicated that a tropane analog of haloperidol with potent D2 binding but designed to avoid the formation of MPP+-like metabolites, such as 4-(4-chlorophenyl)-1-(4-(4-fluorophenyl)-4-oxobutyl)pyridin-1-ium (BCPP+) still produced catalepsy, suggesting a strong role for the D2 receptor in the production of catalepsy in rats, and hence EPS in humans. This study tested the hypothesis that further modifications of the tropane analog to produce compounds with less potent binding to the D2 receptor than haloperidol, would produce less catalepsy. These tests have now revealed that while haloperidol produced maximum catalepsy, these compounds produced moderate to low levels of catalepsy. Compound 9, with the least binding affinity to the D2R, produced the least catalepsy and highest Minimum Adverse Effective Dose (MAED) of the analogs tested regardless of their affinities at other receptors including the 5-HT1AR. These observations support the hypothesis that moderation of the D2 binding of the tropane analogs could reduce catalepsy potential in rats and consequently EPS in man.

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Further evaluation of the tropane analogs of haloperidol

Sampson

Bricker

Xiao-lin

et al. 2014

Bioorganic & Medicinal Chemistry Letters

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“…Our previous work indicated that pyridine and pyrimidine rings impacted binding to CNS receptors. 9–12 Hence, we first explored replacing the 4-chlorophenyl moiety with the pyridine ring in compounds 3–5 to obtain compounds 11–13 (Chart 2) and the binding affinities are reported in Table 2. Compounds 11–13 bind with very high affinities at D 4 versus D 1 –D 3 receptors, and therefore demonstrate decreased selectivity for the D 4 receptor.…”

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“…10–12 A frequent observation in such studies was the fact that unlike the piperidine analogs of haloperidol, the piperazine analogs demonstrated selective and significant affinities to the D 4 receptor subtype. Chart 1 displays common D 4 selective ligands with the piperazine pharmacophore.…”

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Identification of a new selective dopamine D4 receptor ligand

Sampson

Xiao-lin

Eyunni

et al. 2014

Bioorganic & Medicinal Chemistry

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The dopamine D4 receptor has been shown to play key roles in certain CNS pathologies including addiction to cigarette smoking. Thus, selective D4 ligands may be useful in treating some of these conditions. Previous studies in our laboratory have indicated that the piperazine analog of haloperidol exhibits selective and increased affinity to the DAD4 receptor subtype, in comparison to its piperidine analog. This led to further exploration of the piperazine moiety to identify new agents that are selective at the D4 receptor. Compound 27 (KiD4 = 0.84 nM) was the most potent of the compounds tested. However, it only had moderate selectivity for the D4 receptor. Compound 28 (KiD4 = 3.9 nM) while not as potent, was more discriminatory for the D4 receptor subtype. In fact, compound 28 has little or no binding affinity to any of the other four DA receptor subtypes. In addition, of the 23 CNS receptors evaluated, only two, 5HT1AR and 5HT2BR, have binding affinity constants better than 100 nM (Ki < 100 nM). Compound 28 is a potentially useful D4-selective ligand for probing disease treatments involving the D4 receptor, such as assisting smoking cessation, reversing cognitive deficits in schizophrenia and treating erectile dysfunction. Thus, further optimization, functional characterization and evaluation in animal models may be warranted.

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Synthesis and Evaluation of a Series of Piperidine‐2,6‐dione‐piperazine (piperidine) Derivatives as Multireceptor Atypical Antipsychotics

Chen

Liu

et al. 2012

Archiv der Pharmazie

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In this paper, we report the discovery and the synthesis of novel, potential antipsychotic piperidine-2,6-dione derivatives combining potent dopamine D(2) , D(3) and serotonin 5-HT(1A) , 5-HT(2A) , 5-HT(2C) receptor properties. We describe the structure-activity relationships that led us to the promising derivative: 1-(4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)butyl)-4-(4-chlorophenyl)-piperidine-2,6-dione 5. The unique pharmacological features of compound 5 are a high affinity for dopamine D(2) , D(3) and serotonin 5-HT(1A) , 5-HT(2A) , 5-HT(2C) receptors, together with a low affinity for the H(1) receptor (to reduce the risk of obesity under chronic treatment). In a behavioral model predictive of positive symptoms, compound 5 inhibited apomorphine-induced climbing behavior and MK-801-induced hyperactivity with no extrapyramidal symptoms liability in mice. In particular, compound 5 was more potent than clozapine.

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Identification of a butyrophenone analog as a potential atypical antipsychotic agent: 4-[4-(4-Chlorophenyl)-1,4-diazepan-1-yl]-1-(4-fluorophenyl)butan-1-one

Cited by 42 publications

References 46 publications

Further evaluation of the tropane analogs of haloperidol

Further evaluation of the tropane analogs of haloperidol

Identification of a new selective dopamine D4 receptor ligand

Synthesis and Evaluation of a Series of Piperidine‐2,6‐dione‐piperazine (piperidine) Derivatives as Multireceptor Atypical Antipsychotics

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